US6288120B1 - Prevention of loss and restoration of bone mass by certain prostaglandin agonists - Google Patents

Prevention of loss and restoration of bone mass by certain prostaglandin agonists Download PDF

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US6288120B1
US6288120B1 US09/331,081 US33108199A US6288120B1 US 6288120 B1 US6288120 B1 US 6288120B1 US 33108199 A US33108199 A US 33108199A US 6288120 B1 US6288120 B1 US 6288120B1
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alkylene
phenyl
compound
recited
fluoro
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Kimberly O. Cameron
Hua Z. Ke
Bruce A. Lefker
Robert L. Rosati
David D. Thompson
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Pfizer Products Inc
Pfizer Inc
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Pfizer Inc
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Assigned to PFIZER INC., PFIZER PRODUCTS INC. reassignment PFIZER INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CAMERON, KIMBERLY O., KE, HUA Z, LEFKER, BRUCE A., ROSATI, ROBERT L., THOMPSON, DAVID D.
Priority to US09/897,824 priority patent/US6492412B2/en
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Priority to US10/652,188 priority patent/US6998423B2/en
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • This invention relates to prostaglandin agonists, pharmaceutical compositions containing such agonists and the use of such agonists to prevent bone loss or restore or augment bone mass including the treatment of conditions which present with low bone mass in mammals, including humans.
  • Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.
  • the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually.
  • Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being physically impaired.
  • the elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population.
  • Worldwide fracture incidence is forecasted to increase three-fold over the next 60 years, and one study estimated that there will be 4.5 million hip fractures worldwide in 2050.
  • the first is the use of anti-resorptive compounds to reduce the resorption of bone tissue.
  • Estrogen is an example of an anti-resorptive agent. It is known that estrogen reduces fractures. In addition, Black, et al. in EP 0605193A1 report that estrogen, particularly when taken orally, lowers plasma levels of LDL and raises those of the beneficial high density lipoproteins (HDL's). However, estrogen failed to restore bone back to young adult levels in the established osteoporotic skeleton. Furthermore, long-term estrogen therapy, however, has been implicated in a variety of disorders, including an increase in the risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to avoid this treatment. The significant undesirable effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis that have the desirable effect on serum LDL but do not cause undesirable effects.
  • a second type of pharmaceutical therapy for the treatment of osteoporosis is the use of anabolic agents to promote bone formation and increase bone mass. This class of agents is expected to restore bone to the established osteoporotic skeleton.
  • U.S. Pat. No. 4,112,236 discloses certain interphenylene 8-aza-9-dioxothia-11,12-secoprostaglandins for the treatment of patients with renal impairment.
  • Certain prostagladin agonists are disclosed in GB 1478281, GB1479156 and U.S. Pat. Nos. 4,175,203, 4,055,596, 4,175,203, 3,987,091 and 3,991,106 as being useful as, for example, renal vasodilators.
  • U.S. Pat. No. 4,033,996 discloses certain 8-aza-9-oxo(and dioxo)-thia-11,12-secoprostaglandins which are useful as renal vasodilators, for the prevention of thrombus formation, to induce growth hormone release, and as regulators of the immune response.
  • French patent no. 897,566 discloses certain amino acid derivatives for the treatment of neurological, mental or cardiovascular disease.
  • Estrogens have been shown (Bolander et al., 38th Annual Meeting Orthopedic Research Society, 1992) to improve the quality of the healing of appendicular fractures. Therefore, estrogen replacement therapy might appear to be a method for the treatment of fracture repair.
  • patient compliance with estrogen therapy is relatively poor due to its side effects, including the resumption of menses, mastodynia, an increased risk of uterine cancer, an increased perceived risk of breast cancer, and the concomitant use of progestins.
  • men are likely to object to the use of estrogen treatment.
  • Clearly the need exists for a therapy which would be beneficial to patients who have suffered debilitating bone fractures or who have low bone mass and which would increase patient compliance.
  • osteoporosis therapies there is a continuing need and a continuing search in this field of art for alternative osteoporosis therapies.
  • osteoporosis therapies there is a need for bone fracture healing therapies.
  • This invention is directed to a compound of Formula I
  • A is (C 1 -C 6 )alkylsulfonyl, (C 3 -C 7 )cycloalkylsulfonyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkylsulfonyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy, (C 1 -C 4 )alkyl or halo;
  • W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N-(C 1 -C 4 )alkyleneaminosulfonyl-, sulfonylamino, N-(C 1 -C 4 )alkylenesulfonylamino, carboxamido, N-(C 1 -C 4 )alkylenecarboxamido, carboxamidooxy, N-(C 1 -C 4 )alkylenecarboxamidooxy, carbamoyl, -mono-N-(C 1 -C 4 )alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C 1 -C 4 )alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
  • X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C 1 -C 3 )alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C 1 -C 4 )alkoxy, or carbamoyl;
  • Z is carboxyl, (C 1 -C 6 )alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C 1 -C 4 )alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
  • K is a bond, (C 1 -C 8 )alkylene, thio(C 1 -C 4 )alkylene or oxy(C 1 -C 4 )alkylene, said (C 1 -C 8 )alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
  • M is —Ar, —Ar 1 —V—Ar 2 , —Ar 1 —S—Ar 2 or —Ar 1 —O—Ar 2
  • Ar, Ar 1 and Ar 2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • Ar, Ar 1 and Ar 2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R 1 , R 2 and R 3 wherein R 1 , R 2 and R 3 are hydroxy, nitro, halo, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkanoyl, formyl, (C 1 -C 8 )alkanoyl, (C 1 -C 6 )al
  • R 1 , R 2 and R 3 are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy;
  • V is a bond or (C 1 -C 3 )alkylene optionally mono- or di-substituted independently with hydroxy or fluoro
  • A is (C 1 -C 6 )alkanoyl, or (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkanoyl, said A moieties optionally mono-, di- or tri-substituted independently on carbon with hydroxy or halo;
  • W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N-(C 1 -C 4 )alkyleneaminosulfonyl-, sulfonylamino, N-(C 1 -C 4 )alkylenesulfonylamino, carboxamido, N-(C 1 -C 4 )alkylenecarboxamido, carboxamidooxy, N-(C 1 -C 4 )alkylenecarboxamidooxy, carbamoyl, -mono-N-(C 1 -C 4 )alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C 1 -C 4 )alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
  • X is a five or six membered aromatic ring optionally having one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C 1 -C 3 )alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C 1 -C 4 )alkoxy, or carbamoyl;
  • Z is carboxyl, (C 1 -C 6 )alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C 1 -C 4 )alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
  • K is (C 1 -C 8 )alkylene, thio(C 1 -C 4 )alkylene or oxy(C 1 -C 4 )alkylene, said (C 1 -C 8 )alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
  • M is —Ar, —Ar 1 —V—Ar, —Ar 1 —S—Ar 2 or —Ar 1 —O—Ar 2
  • Ar, Ar 1 and Ar 2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • Ar, Ar 1 and Ar 2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R 1 , R 2 and R 3 wherein R 1 , R 2 and R 3 are H, hydroxy, nitro, halo, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkanoyl, formyl, (C 1 -C 8 )alkanoyl, (C 1 -C 6
  • R 1 , R 2 and R 3 are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy;
  • V is a bond or (C 1 -C 3 )alkylene optionally mono- or di-substituted independently with hydroxy or fluoro
  • A is (C 1 -C 6 )alkanoyl, or (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkanoyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy or halo;
  • W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N-(C 1 -C 4 )alkyleneaminosulfonyl-, sulfonylamino, N-(C 1 -C 4 )alkylenesulfonylamino, carboxamido, N-(C 1 -C 4 )alkylenecarboxamido, carboxamidooxy, N-(C 1 -C 4 )alkylenecarboxamidooxy, carbamoyl, -mono-N-(C 1 -C 4 )alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C 1 -C 4 )alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
  • X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen and sulfur, said ring optionally mono-, or di-substituted independently with halo, (C 1 -C 3 )alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C 1 -C 4 )alkoxy, or carbamoyl;
  • Z is carboxyl, (C 1 -C 6 )alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyi, (C 1 -C 4 )alkylsulfonylcarbamoyl or phenyisulfonylcarbamoyl;
  • K is a bond, (C 1 -C 8 )alkylene, thio(C 1 -C 4 )alkylene, (C 4 -C 7 )cycloalkyl(C 1 -C 6 )alkylene or oxy(C 1 -C 4 )alkylene, said (C 1 -C 8 )alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
  • M is —Ar, —Ar 1 —V—Ar 2 , —Ar 1 —S—Ar 2 or —Ar 1 —O—Ar 2
  • Ar, Ar 1 and Ar 2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • Ar, Ar 1 and Ar 2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R 1 , R 2 and R 3 wherein R 1 , R 2 and R 3 are H, hydroxy, nitro, halo, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkanoyl, formyl, (C 1 -C 8 )alkanoyl, (C 1 -C 6
  • R 1 , R 2 and R 3 are optionally mono-, di- or tri-substituted independently on carbon with halo or hydroxy;
  • V is a bond or (C 1 -C 3 )alkylene optionally mono- or di-substituted independently with hydroxy or fluoro
  • a preferred group of compounds designated the A Group, contains those compounds having the Formula I as shown above wherein
  • A is (C 1 -C 6 )alkylsulfonyl, (C 3 -C 6 )cycloalkylsulfonyl or (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkylsulfonyl, said A moieties optionally mono-, di-, or tri-substituted on carbon with fluoro;
  • X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;
  • W is oxy, thio or sulfonyl
  • Z is carboxyl, (C 1 -C 4 )alkoxycarbonyl orterazolyl;
  • K is methylene or ethylene
  • Ar, Ar 1 and Ar 2 are each independently (C 5 -C 7 )cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl;
  • R 1 is halo, (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, said (C 1 -C 6 )alkoxy, C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and
  • R 2 and R 3 are chioro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
  • a group of compounds which is preferred among the A Group of compounds designated the B Group contains those compounds wherein
  • A is (C 1 -C 3 )alkylsulfonyl
  • M is —Ar 1 —V—Ar 2 or —Ar 1 —O—Ar 2 wherein Ar 1 and Ar 2 are each independently phenyl, pyridyl or thienyl;
  • V is a bond or (C 1 -C 2 )alkylene
  • R 1 is chloro, fluoro, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy, said (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
  • R 2 and R 3 are each independently chloro or fluoro.
  • Especially preferred compounds within the B Group of compounds are compounds wherein
  • A is methylsulfonyl
  • Q is n-hexylene
  • Z is carboxyl
  • K is methylene
  • M is 4-(2-hydroxymethylphenyl)phenyl
  • A is methylsulfonyl
  • Q is n-hexylene
  • Z is carboxyl
  • K is methylene
  • M is 4-(3-hydroxymethylthien-2-yl)phenyl
  • A is methylsulfonyl
  • Q is n-hexylene
  • Z is carboxyl
  • K is methylene
  • M is 4-(2-chlorophenyl)phenyl.
  • a preferred group of compounds designated the C Group, contains those compounds having the Formula I as shown above wherein
  • A is (C 1 -C 6 )alkylsulfonyl, (C 3 -C 6 )cycloalkylsulfonyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkylsulfonyl;
  • X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethyloxy;
  • W is oxy, thio or sulfonyl
  • Z is carboxyl, (C 1 -C 4 )alkoxycarbonyl or tetrazolyl;
  • K is (C 1 -C 8 )alkylene or oxy(C 1 -C 4 )alkylene, said (C 1 -C 8 )alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro;
  • M is —Ar, said —Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, cyclobutyl, cycloheptyl or chroman
  • R 1 is halo, (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, said (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, optionally mono-, di- or tri-substituted
  • R 2 and R 3 are each independently hydroxy, halo, trifluoromethyl, (C 1 -C 7 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 5 )alkanoyl, cyano, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, formyl, difluoromethoxy, trifluoromethoxy or carbamoyl.
  • Group C compounds that K is not optionally mono-, di- or tri-subsfituted independently with methyl, fluoro or chloro.
  • a group of compounds which is preferred among the C Group of compounds, designated the D Group, contains those compounds wherein
  • K is methylene
  • A is (C 1 -C 3 )alkylsulfonyl
  • M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein —Ar is substituted with at least R 1 ;
  • R 1 is (C 1 -C 7 )alkyl or (C 1 -C 5 )alkoxy, said (C 1 -C 7 )alkyl or (C 1 -C 5 )alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
  • R 2 and R 3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
  • a group of compounds which is preferred among the D Group of compounds, designated the E Group, contains those compounds wherein
  • Q is -(C 2 -C 6 )alkylene-W-(C 1 -C 3 )alkylene-;
  • W is oxy.
  • a group of compounds which is preferred among the D Group of compounds, designated the F Group, contains those compounds wherein
  • Q is -(C 3 -C 8 )alkylene-, said -(C 3 -C 8 )alkylene- optionally substituted with from one to four fluorines.
  • A is methylsulfonyl
  • Q is n-hexylene
  • Z is carboxyl
  • K is methylene
  • M is 4-(1-hydroxy-n-hexylene-1-yl)phenyl
  • A is methylsulfonyl
  • Q is n-hexylene
  • Z is carboxyl
  • K is methylene
  • M is 4-(n-butylene-1-yl)phenyl
  • A is methylsulfonyl
  • Q is n-hexylene
  • Z is carboxyl
  • K is methylene
  • M is 5-(1-hydroxy-n-hexylene-1-yl)thien-2-yl.
  • a group of compounds which is preferred among the D Group of compounds, designated the G Group, contains those compounds wherein
  • Q is -X-(C 1 -C 5 )alkylene-
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the D Group of compounds, designated the H Group, contains those compounds wherein
  • Q is -(C 1 -C 5 )alkylene-X-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the D Group of compounds, designated the I Group, contains those compounds wherein
  • Q is -(C 1 -C 3 )alkylene-X-(C 1 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • An especially preferred compound within the I Group of compounds is a compound wherein
  • A is methylsulfonyl
  • Z is carboxyl
  • K is methylene
  • M is 4-(n-butylene-1-yl)phenyl.
  • a group of compounds which is preferred among the D Group of compounds, designated the J Group, contains those compounds wherein
  • Q is -(C 2 -C 4 )alkylene-W-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
  • W is oxy.
  • a group of compounds which is preferred among the D Group of compounds, designated the K Group, contains those compounds wherein
  • Q is -(C 0 -C 4 )alkylene-X-W-(C 1 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
  • W is oxy.
  • a group of compounds which is preferred among the D Group of compounds, designated the L Group, contains those compounds wherein
  • Q is -(C 2 -C 4 )alkylene-W-X-W-(C 1 -C 3 )alkylene-;
  • W is oxy
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trfluoromethyl or methoxy.
  • a group of compounds which is preferred among the D Group of compounds, designated the M Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethenylene-(C 1 -C 4 )alkylene-;
  • M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.
  • a group of compounds which is preferred among the D Group of compounds, designated the N Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethenylene-(C 0 -C 2 )alkylene-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the D Group of compounds, designated the O Group, contains those compounds wherein
  • Q is -(C 1 -C 3 )alkylene-ethenylene-(C 0 -C 2 )alkylene-X-W-(C 1 -C 3 )alkylene-;
  • W is oxy
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the D Group of compounds, designated the P Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethynylene-(C 1 -C 4 )alkylene-.
  • a group of compounds which is preferred among the D Group of compounds designated the Q Group contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethynylene-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the C Group of compounds designated the R Group contains those compounds wherein
  • A is (C 1 -C 3 )alkylsulfonyl
  • K is (C 1 -C 8 )alkylene
  • —Ar is phenyl, thiazolyl, pyridyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxine, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and
  • R 1 , R 2 and R 3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 4 )alkoxy or (C 1 -C 7 )alkyl.
  • a group of compounds which is preferred among the R Group of compounds, designated the S Group, contains those compounds wherein
  • Q is -(C 2 -C 6 )alkylene-W-(C 1 -C 3 )alkylene-;
  • W is oxy.
  • a group of compounds which is preferred among the R Group of compounds, designated the T Group, contains those compounds wherein
  • Q is -(C 3 -C 8 )alkylene-, said -(C 3 -C 8 )alkylene- optionally substituted with from one to four fluorines.
  • Especially preferred compounds among the T Group are compounds wherein
  • A is methylsulfonyl
  • Q is n-hexylene
  • Z is carboxyl
  • K is propylene
  • M is 3-chlorophenyl
  • A is methylsulfonyl
  • Q is n-hexylene
  • Z is carboxyl
  • K is propylene
  • M is 3,5-dichlorophenyl.
  • a group of compounds which is preferred among the R Group of compounds, designated the U Group, contains those compounds wherein
  • Q is -X-(C 1 -C 5 )alkylene-
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trnfluoromethyl or methoxy.
  • a group of compounds which is preferred among the R Group of compounds, designated the V Group, contains those compounds wherein
  • Q is -(C 1 -C 5 )alkylene-X-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • An especially preferred compound among the V group is a compound wherein
  • A is methylsulfonyl
  • Q-Z is 3-(2-carboxylthien-5-yl)-n-propylene
  • K is propylene
  • M is 3-chlorophenyl.
  • a group of compounds which is preferred among the R Group of compounds, designated the W Group, contains those compounds wherein
  • Q is -(C 1 -C 3 )alkylene-X-(C 1 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the R Group of compounds, designated the X Group, contains those compounds wherein
  • Q is -(C 2 -C 4 )alkylene-W-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
  • W is oxy.
  • a group of compounds which is preferred among the R Group of compounds, designated the Y Group, contains those compounds wherein
  • Q is -(C 0 -C 4 )alkylene-X-W-(C 1 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
  • W is oxy.
  • a group of compounds which is preferred among the R Group of compounds, designated the Z Group, contains those compounds wherein
  • Q is -(C 2 -C 4 )alkyiene-W-X-W-(C 1 -C 3 )alkylene-;
  • W is oxy
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the R Group of compounds, designated the A1 Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethenylene-(C 1 -C 4 )alkylene-;
  • M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.
  • a group of compounds which is preferred among the R Group of compounds, designated the B1 Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethenylene-(C 0 -C 2 )alkylene-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the R Group of compounds, designated the C1 Group, contains those compounds wherein
  • Q is -(C 1 -C 3 )alkylene-ethenylene-(C 0 -C 2 )alkylene-X-W-(C 1 -C 3 )alkylene-;
  • W is oxy
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the R Group of compounds, designated the D1 Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethynylene-(C 1 -C 4 )alkylene-.
  • a group of compounds which is preferred among the R Group of compounds, designated the E1 Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethynylene-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the C Group of compounds, designated the F1 Group, contains those compounds wherein
  • A is (C 1 -C 3 )alkylsulfonyl
  • K is oxy(C 1 -C 4 )alkylene
  • —Ar is phenyl, thienyl, thiazolyl, pyridyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl;
  • R 1 , R 2 and R 3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 4 )alkoxy or (C 1 -C 7 )alkyl.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the G1 group, contains those compounds wherein
  • Q is -(C 2 -C 6 )alkylene-W-(C 1 -C 3 )alkylene-;
  • W is oxy.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the H1 Group, contains those compounds wherein
  • Q is -(C 3 -C 8 )alkylene-, said -(C 3 -C 8 )alkylene- optionally substituted with from one to four fluorines.
  • An especially preferred compound among the H1 group of compounds is a compound wherein
  • A is methylsulfonyl
  • Q is n-hexylene
  • Z is carboxyl
  • K is oxyethylene
  • M is 3,5-dichlorophenyl.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the I1 Group, contains those compounds wherein
  • Q is -X-(C 1 -C 5 )alkylene-
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the J1 Group, contains those compounds wherein
  • Q is -(C 1 -C 5 )alkylene-X-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • An especially preferred compound among the J1 group is a compound wherein
  • A is methylsulfonyl
  • Q-Z is 3-(2-carboxylthien-5-yl)-n-propylene
  • K is oxyethylene
  • M is 3,5-dichlorophenyl.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the K1 Group, contains those compounds wherein
  • Q is -(C 1 -C 3 )alkylene-X-(C 1 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the L1 Group, contains those compounds wherein
  • Q is -(C 2 -C 4 )alkylene-W-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
  • W is oxy.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the M1 Group, contains those compounds wherein
  • Q is -(C 0 -C 4 )alkylene-X-W-(C 1 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the N1 Group, contains those compounds wherein
  • Q is -(C 2 -C 4 )alkylene-W-X-W-(C 1 -C 3 )alkylene-;
  • W is oxy
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the O1 Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethenylene-(C 1 -C 4 )alkylene-;
  • M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the P1 Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethenylene-(C 0 -C 2 )alkylene-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the Q1 Group, contains those compounds wherein
  • Q is -(C 1 -C 3 )alkylene-ethenylene-(C 0 -C 2 )alkylene-X-W-(C 1 -C 3 )alkylene-;
  • W is oxy
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the Ri Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethynylene-(C 1 -C 4 )alkylene-.
  • a group of compounds which is preferred among the F1 Group of compounds, designated the S1 Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethynylene-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the C1 Group of compounds, designated the T1 Group, contains those compounds wherein
  • A is (C 1 -C 3 )alkylsulfonyl
  • K is (C 3 -C 8 )alkylene, said (C 3 -C 8 )alkylene being mono-unsaturated;
  • Ar is phenyl, thienyl, thiazolyl, pyridyl, cyclopentyl or cyclohexyl;
  • R 1 , R 2 and R 3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 4 )alkoxy or (C 1 -C 7 )alkyl.
  • a group of compounds which is preferred among the T1 Group of compounds, designated the U1 Group, contains those compounds wherein
  • Q is -(C 2 -C 6 )alkylene-W-(C 1 -C 3 )alkylene-;
  • W is oxy.
  • An especially preferred compound among the U1 group is a compound wherein
  • A is methylsulfonyl
  • Q is methyloxy-n-butylene
  • Z is carboxyl
  • K is trans-2-n-propenylene
  • M is 3,5-dichlorophenyl.
  • a group of compounds which is preferred among the T1 Group of compounds, designated the V1 Group, contains those compounds wherein
  • Q is -(C 3 -C 8 )alkylene-, said -(C 3 -C 8 )alkylene- optionally substituted with from one to four fluorines.
  • a preferred compound among the V1 group of compound is a compound wherein
  • A is methylsulfonyl
  • Q is n-hexylene
  • K is trans-2-n-propeneylene
  • M is 3,5-dichlorophenyl.
  • a group of compounds which is preferred among the T1 Group of compounds, designated the W1 Group, contains those compounds wherein
  • Q is -X-(C 1 -C 5 )alkylene-
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the T1 Group of compounds, designated the X1 Group, contains those compounds wherein
  • Q is -(C 1 -C 5 )alkylene-X-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a preferred compound among the X1 Group is a compound wherein
  • A is methylsulfonyl
  • Q-Z is 3-(2-carboxylthien-5yl)-n-propylene
  • K is trans-2-n-propeneylene
  • M is 3,5-dichlorophenyl.
  • a group of compounds which is preferred among the T1 Group of compounds, designated the Y1 Group, contains those compounds wherein
  • Q is -(C 1 -C 3 )alkylene-X-(C 1 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the T1 Group of compounds, designated the Z1 Group, contains those compounds wherein
  • Q is -(C 2 -C 4 )alkylene-W-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chioro, trifluoromethyl or methoxy; and
  • W is oxy.
  • a group of compounds which is preferred among the T1 Group of ompounds, designated the A2 Group, contains those compounds wherein
  • Q is -(C 0 -C 4 )alkylene-X-W-(C 1 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
  • W is oxy.
  • a group of compounds which is preferred among the T1 Group of ompounds, designated the B2 Group, contains those compounds wherein
  • Q is -(C 2 -C 4 )alkylene-W-X-W-(C 1 -C 3 )alkylene-;
  • W is oxy
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the T1 Group of compounds, designated the C2 Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethenylene-(C 1 -C 4 )alkylene-;
  • M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.
  • a group of compounds which is preferred among the T1 Group of compounds, designated the D2 Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethenylene-(C 0 -C 2 )alkylene-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chioro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the T1 Group of compounds, designated the E2 Group, contains those compounds wherein
  • Q is -(C 1 -C 3 )alkylene-ethenylene-(C 0 -C 2 )alkylene-X-W-(C 1 -C 3 )alkylene-;
  • W is oxy
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a group of compounds which is preferred among the T1 Group of compounds, designated the F2 Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethynylene-(C 1 -C 4 )alkylene-.
  • a group of compounds which is preferred among the T1 Group of compounds, designated the G2 Group, contains those compounds wherein
  • Q is -(C 1 -C 4 )alkylene-ethynylene-X-(C 0 -C 3 )alkylene-;
  • X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
  • a preferred group of compounds designated the H2 Group, contains those compounds having the Formula I as shown above wherein
  • A is (C 1 -C 6 )alkanoyl, or (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkanoyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy or halo;
  • X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;
  • W is oxy, thio or sulfonyl
  • Z is carboxyl, (C 1 -C 4 )alkoxycarbonyl or tetrazolyl;
  • K is (C 1 -C 8 )alkylene or oxy(C 1 -C 4 )alkylene, said (C 1 -C 8 )alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro;
  • Ar is (C 5 -C 7 )cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, or chromanyl;
  • Ar 1 and Ar 2 are each independently (C 5 -C 7 )cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl;
  • R 1 is halo, (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, said (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and
  • R 2 and R 3 are each independently hydroxy, halo, difluoromethoxy, trifluoromethoxy, trifluoromethyl, (C 1 -C 7 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 5 )alkanoyl, cyano, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, formyl or carbamoyl.
  • K is not optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro.
  • a group of compounds which is preferred among the H2 Group of compounds, designated the 12 Group, contains those compounds wherein
  • A is (C 1 -C 6 )alkanoyl, said (C 1 -C 6 )alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
  • K is methylene or ethylene
  • M is —Ar 1 —V—Ar 2 or —Ar 1 —O—Ar 2 wherein Ar 1 and Ar 2 are each independently phenyl, pyridyl or thienyl;
  • V is a bond or (C 1 -C 2 )alkylene
  • R 1 is chloro, fluoro, (C 1 -C 4 )alkyl or (C 1 -C 6 )alkoxy, said (C 1 -C 4 )alkyl and (C 1 -C 6 )alkoxy optionally mono-, di-or tri-substituted independently with hydroxy or fluoro; and
  • R 2 and R 3 are each independently chloro or fluoro.
  • a group of compounds which is preferred among the H2 Group of compounds, designated the J2 Group, contains those compounds wherein
  • A is (C 1 -C 6 )alkanoyl said (C 1 -C 6 )alkanoyl optonally mono-, di- or tri-substituted independently on carbon with hydroxy or halo;
  • K is methylene
  • M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein —Ar is substituted with at least R 1 ;
  • R 1 is (C 1 -C 7 )alkyl or (C 1 -C 5 )alkoxy, said (C 1 -C 7 )alkyl or (C 1 -C 5 )alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
  • R 2 and R 3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
  • a group of compounds which is preferred among the H2 Group of compounds, designated the K2 Group, contains those compounds wherein
  • A is (C 1 -C 6 )alkanoyl, said (C 1 -C 6 )alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
  • K is (C 1 -C 8 )alkylene
  • M is —Ar and —Ar is phenyl, thienyl, benzofuranyl, benzo[1 ,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and
  • R 1 , R 2 and R 3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 4 )alkoxy or (C 1 -C 7 )alkyl.
  • a group of compounds which is preferred among the H2 Group of compounds, designated the L2 Group, contains those compounds wherein
  • A is (C 1 -C 6 )alkanoyl, said (C 1 -C 6 )alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
  • K is oxy(C 1 -C 4 )alkylene
  • M is —Ar and —Ar is phenyl, thienyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and
  • R 1 , R 2 and R 3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 4 )alkoxy or (C 1 -C 7 )alkyl.
  • a group of compounds which is preferred among the H2 Group of compounds, designated the M2 Group, contains those compounds wherein
  • A is (C 3 -C 6 )alkanoyl said (C 3 -C 6 )alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
  • K is (C 3 -C 8 )alkylene, said (C 3 -C 8 )alkylene being mono-unsaturated;
  • M is —Ar and —Ar is phenyl, thienyl, cyclopentyl or cyclohexyl;
  • R 1 , R 2 and R 3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )alkoxy or (C 1 -C 7 )alkyl.
  • N2 Group contains those compounds having the Formula I as shown above wherein
  • A is (C 1 -C 6 )alkanoyl, or (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkanoyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy or halo;
  • X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;
  • W is oxy, thio or sulfonyl
  • Z is carboxyl, (C 1 -C 4 )alkoxycarbonyl or tetrazolyl;
  • K is (C 1 -C 8 )alkylene or oxy(C 1 -C 4 )alkylene, said (C 1 -C 8 )alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro;
  • Ar is (C 5 -C 7 )cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, or chromanyl;
  • Ar 1 and Ar 2 are each independently (C 5 -C 7 )cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl;
  • R 1 is halo, (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, said (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and
  • R 2 and R 3 are each independently hydroxy, halo, difluoromethoxy, trifluoromethoxy, trifluoromethyl, (C 1 -C 7 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 5 )alkanoyl, cyano, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, formyl or carbamoyl.
  • K is not optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro.
  • a group of compounds which is preferred among the N2 Group of compounds, designated the O2 Group, contains those compounds wherein
  • A is (C 1 -C 6 )alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with halo;
  • K is methylene or ethylene
  • M is —Ar 1 —V—Ar 2 or —Ar 1 —O—Ar 2 wherein Ar 1 and Ar 2 are each independently phenyl, pyridyl or thienyl;
  • V is a bond or (C 1 -C 2 )alkylene
  • R 1 is chloro, fluoro, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy, said (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy optionally mono-, di-or tri-substituted independently with hydroxy or fluoro; and
  • R 2 and R 3 are each independently chloro or fluoro.
  • compounds, designated the P2 Group contains those compounds wherein A is (C 1 -C 6 )alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with hydroxy or halo;
  • K is methylene
  • M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein —Ar is substituted with at least R 1 ;
  • R 1 is (C 1 -C 7 )alkyl or (C 1 -C 6 )alkoxy, said (C 1 -C 7 )alkyl or (C 1 -C 6 )alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
  • R 2 and R 3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
  • a group of compounds which is preferred among the N2 Group of compounds, designated the Q2 Group, contains those compounds wherein
  • A is (C 1 -C 6 )alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with halo;
  • K is (C 1 -C 8 )alkylene
  • M is —Ar and —Ar is phenyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and
  • R 1 , R 2 and R 3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )alkoxy or (C 1 -C 7 )alkyl.
  • R 2 Group contains those compounds wherein
  • A is (C 1 -C 6 )alkanoyl said A optionally mono, di- or tri-substituted on carbon independently with halo;
  • K is oxy(C 1 -C 4 )alkylene
  • M is —Ar and —Ar is phenyl, thienyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and
  • R 1 , R 2 and R 3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )alkoxy or (C 1 -C 7 )alkyl.
  • a group of compounds which is preferred among the N2 Group of compounds, designated the S2 Group, contains those compounds wherein
  • A is (C 1 -C 6 )alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with halo;
  • K is (C 3 -C 8 )alkylene, said (C 3 -C 8 )alkylene being mono-unsaturated;
  • M is —Ar and —Ar is phenyl, thienyl, cyclopentyl or cyclohexyl;
  • R 1 , R 2 and R 3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )alkoxy or (C 1 -C 7 )alkyl.
  • An especially preferred compound of the J2 Group of compounds is a compound wherein
  • A is propanoyl
  • Q is n-hexylene
  • Z is carboxyl
  • K is methylene
  • M is 4-(n-1-hydroxylhexyl)phenyl.
  • An especially preferred compound among the H1 Group of compounds is a compound wherein
  • A is methylsulfonyl
  • Q is n-hexylene
  • K is oxyethyl
  • M is 3,5-dichlorophenyl.
  • An especially preferred compound among the Y1 Group of compounds is a compound wherein
  • A is methylsulfonyl
  • Z is carboxyl
  • K is trans-2-n-propenylene
  • M is 3,5-dichlorophenyl.
  • This invention is also directed to a method for augmenting, and maintaining bone mass and preventing further bone loss in a mammal comprising administering to a mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof.
  • This invention is also directed to a method for treating a mammal having a condition which presents with low bone mass comprising administering to a mammal having a condition which presents with low bone mass a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof.
  • a mammal having a condition which presents with low bone mass a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof.
  • Preferably post-menopausal women and men over the age of 60 are treated.
  • individuals regardless of age who have significantly reduced bone mass, i.e., ⁇ 1.5 s.d. below young normal levels.
  • Yet another aspect of this invention is directed to methods for treating osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a mammal (including a human being) comprising administering to a mammal suffering from osteoporosis, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth an osteoporosis, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating osteoporosis in a mammal (including a human being) by comprising administering to a mammal suffering from osteoporosis an osteoporosis treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating osteotomy bone loss in a mammal (including a human being) comprising administering to a mammal who underwent an osteotomy procedure to repair bone integrity a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • the Formula I compound is applied locally to a site of osteotomy.
  • Yet another aspect of this invention is directed to a method for treating alveolar bone loss in a mammal (including a human being) comprising administering to a mammal suffering from an alveolar bone loss an alveolar bone loss treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating bone loss associated with periodontitis in a mammal (including a human being) comprising administering to a mammal suffering from bone loss associated with periodontitis a bone loss associated with periodontitis treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating childhood idiopathic bone loss in a mammal comprising administering to a child suffering from childhood idiopathic bone loss a childhood idiopathic bone loss treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating “secondary osteoporosis”, which includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in a mammal (including a human being) by administering to a mammal suffering from “secondary osteoporosis” a “secondary osteoporosis” treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating glucocorticoid-induced osteoporosis in a mammal (including a human being) comprising administering to a mammal suffering from glucocorticoid-induced osteoporosis a glucocorticoid-induced osteoporosis treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating hyperthyroidism-induced osteoporosis in a mammal (including a human being) comprising administering to a mammal suffering from hyperthyroidism-induced osteoporosis a hyperthyroidism-induced osteoporosis treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating immobilization-induced osteoporosis in a mammal (including a human being) comprising administering to a mammal suffering from immobilization-induced osteoporosis a immobilization-induced osteoporosis treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating heparin-induced osteoporosis in a mammal (including a human being) comprising administering to a mammal suffering from heparin-induced osteoporosis a heparin-induced osteoporosis treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating immunosuppressive-induced osteoporosis in a mammal (including a human being) comprising administering to a mammal suffering from immunosuppressive-induced osteoporosis an immunosuppressive-induced osteoporosis treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating a bone fracture in a mammal (including a human being) comprising administering to a mammal suffering from a bone fracture a bone fracture treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • a bone fracture comprising administering to a mammal suffering from a bone fracture a bone fracture treating amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof is applied locally to the site of bone fracture.
  • the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof is administered systemically.
  • Yet another aspect of this invention is directed to a method for enhancing bone healing following facial reconstruction or maxillary reconstruction or mandibular reconstruction in a mammal (including a human being) comprising administering to a mammal which has undergone facial reconstruction or maxillary reconstruction or mandibular reconstruction a bone enhancing amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof is applied locally to the site of bone reconstruction.
  • Yet another aspect of this invention is directed to a method for inducing prosthetic ingrowth in a mammal (including a human being) comprising administering to a mammal a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for inducing vertebral synostosis in a mammal (including a human being) comprising administering to a mammal undergoing surgery for vertebral synostosis a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for enhancing long bone extension in a mammal (including a human being) comprising administering to a mammal suffering from an insufficiently sized long bone a long bone enhancing amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for use in place of a bone graft in a mammal (including a human being) comprising administering to a mammal a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof is applied locally to the site of a bone graft.
  • an amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof can be applied to the site of a bone graft to restore bone.
  • a preferred dosage is about 0.001 to 100 mg/kg/day of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • An especially preferred dosage is about 0.01 to 10 mg/kg/day of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.
  • compositions which comprise a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • compositions for the augmentation of bone mass which comprise a bone mass augmentating amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • compositions for the treatment of a condition which presents with low bone mass in a mammal which comprise a low bone mass condition treating amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, bone graft substitution or prosthetic ingrowth in a mammal (including a human being) which comprises a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of “secondary osteoporosis”, which includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in a mammal (including a human being) which comprise a “secondary osteoporosis” treating amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of osteoporosis in a mammal (including a human being) which comprise an osteoporosis treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for enhancing bone fracture healing in a mammal (including a human being) which comprise a bone fracture treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of osteotomy bone loss in a mammal (including a human being) which comprise an osteotomy bone loss treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • compositions for the treatment of alveolar bone loss in a mammal which comprise an alveolar bone loss treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of childhood idiopathic bone loss in a child which comprises a childhood idiopathic bone loss treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • compositions for the augmentation of bone healing following facial reconstruction or maxillary reconstruction or mandibular reconstruction in a mammal which comprise a bone healing treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of bone loss associated with periodontitis in a mammal (including a human being) which comprise a bone loss associated with periodontitis treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of prosthetic ingrowth in a mammal (including a human being) which comprise a prosthetic ingrowth treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for inducing vertebral synostosis in a mammal (including a human being) which comprise a therapeutically effective amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the augmentation of long bone extension in a mammal (including a human being) which comprise bone mass augmentation treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of glucocorticoid-induced osteoporosis in a mammal (including a human being) which comprise a glucocorticoid-induced osteoporosis treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of hyperthyroidism-induced osteoporosis in a mammal (including a human being) which comprise a hyperthyroidism-induced osteoporosis treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of immobilization-induced osteoporosis in a mammal (including a human being) which comprise a immobilization-induced osteoporosis treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of heparin-induced osteoporosis in a mammal (including a human being) which comprise a heparin-induced osteoporosis treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of immunosuppressive-induced osteoporosis in a mammal (including a human being) which comprise a immunosuppressive-induced osteoporosis treating amount of a compound of the Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • Yet another aspect of this invention is directed to a pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof and an anti-resorptive agent and for the use of such compositions for the treatment (e.g., prevention) of conditions which present with low bone mass, including osteoporosis in mammals (e.g., humans, particularly women) or the use of such compositions for other bone mass augmenting uses.
  • the combinations of this invention comprises a therapeutically effective amount of a first compound, said first compound being a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof; and a therapeutically effective amount of a second compound, said second compound being an anti-resorptive agent such as an estrogen agonist/antagonist or a bisphosphonate.
  • Preferred estrogen agonist/antagonists include droloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman, levormeloxifene, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, ⁇ 4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl ⁇ -[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,
  • Especially preferred estrogen agonisttantagonists include droloxifene
  • Preferred bisphosphonates include, tiludronic acid, alendronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid and their pharmaceutically acceptable salts.
  • Another aspect of this invention is a method for treating mammals which present with low bone mass comprising administering to a mammal having a condition which presents with low bone mass
  • a therapeutically effective amount of a second compound said second compound being an anti-resorptive agent such as an estrogen agonistlantagonist or a bisphosphonate.
  • compositions and methods may also be used for other bone mass augmenting uses.
  • Preferred estrogen agonistlantagonists in this method include droloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman, levormeloxifene, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, ⁇ 4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl ⁇ [6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;
  • Especially preferred estrogen agonistlantagonists include droloxifene
  • Preferred bisphosphonates include, tiludronic acid, alendronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid and their pharmaceutically acceptable salts.
  • a preferred aspect of this method is wherein the condition which presents with low bone mass is osteoporosis.
  • Another preferred aspect of this method is wherein the first compound and the second compound are administered substantially simultaneously.
  • Another preferred aspect of this method is wherein the first compound is administered for a period of from about one week to about three years.
  • the administration of the first compound is followed by administration of the second compound wherein the second compound is an estrogen agonist/antagonist for a period of from about three months to about three years without the administration of the first compound during the second period of from about three months to about three years.
  • the administration of the first compound is followed by administration of the second compound wherein the second compound is an estrogen agonist/antagonist for a period greater than about three years without the administration of the first compound during the greater than about three year period.
  • Another aspect of this invention is a kit comprising:
  • a a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in a first unit dosage form;
  • an anti-resorptive agent such as an estrogen agonisttantagonist or a bisphosphonate and a pharmaceutically acceptable carrier in a second unit dosage form
  • container means for containing said first and second dosage forms.
  • Preferred estrogen agonist/antagonists in this kit include droloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman, levormeloxifene, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, ⁇ 4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl ⁇ -[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,
  • Especially preferred estrogen agonist/antagonists include droloxifene
  • Preferred bisphosphonates include, tiludronic acid, alendronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid and their pharmaceutically acceptable salts.
  • Yet another aspect of this invention is directed to a pharmaceutical composition including a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof and another bone anabolic agent (although the other bone anabolic agent may be a different Formula I compound) and for the use of such compositions for the treatment of conditions which present with low bone mass, including osteoporosis in mammals (e.g., humans, particularly women) or the use of such compositions for other bone mass augmenting uses.
  • a pharmaceutical composition including a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof and another bone anabolic agent (although the other bone anabolic agent may be a different Formula I compound) and for the use of such compositions for the treatment of conditions which present with low bone mass, including osteoporosis in mammals (e.g., humans, particularly women) or the use of such compositions for other bone mass augmenting uses.
  • the combination comprises a therapeutically effective amount of a first compound, said first compound being a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof; and a therapeutically effective amount of a second compound, said second compound being another bone anabolic agent.
  • Preferred bone anabolic agents include IGF-1 optionally with IGF-1 binding protein 3, prostaglandin, prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, parathyroid hormone related peptides and active fragments and analogues of parathyroid hormone related peptides, growth hormone or growth hormone secretagogues and the pharmaceutically acceptable salts thereof.
  • Another aspect of this invention is a method for treating mammals which present with low bone mass comprising administering to a mammal having a condition which presents with low bone mass
  • compositions and methods may also be used for other bone mass augmenting uses.
  • Preferred bone anabolic agents include IGF-1 optionally with IGF-1 binding protein 3, prostaglandin, prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, parathyroid hormone related peptides and active fragments and analogues of parathyroid hormone related peptides, growth hormone or growth hormone secretagogues and the pharmaceutically acceptable salts thereof
  • a preferred aspect of this method is wherein the condition which presents with low bone mass is osteoporosis.
  • Another preferred aspect of this method is wherein the first compound and the second compound are administered substantially simultaneously.
  • Another aspect of this invention is a kit comprising:
  • a a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in a first unit dosage form;
  • container means for containing said first and second dosage forms.
  • Preferred bone anabolic agents include IGF-1 optionally with IGF-1 binding protein 3, prostaglandin, prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, parathyroid hormone related peptides and active fragments and analogues of parathyroid hormone related peptides, growth hormone or growth hormone secretagogues and the pharmaceutically acceptable salts thereof.
  • T2 Group contains those compounds having the Formula I as shown above wherein
  • A is (C 1 -C 3 ) alkylsulfonyl
  • M is —Ar 1 —V—Ar 2 or —Ar 1 —O—Ar 2 ;
  • V is a bond or —CH 2 —
  • Z is carboxyl, (C 1 -C 4 )alkoxycarbonyl or tetrazolyl;
  • X is thienyl, thiazolyl, or furanyl
  • K is methylene
  • Ar 1 is phenyl, (C 5 -C 7 )cycloalkyl, furanyl, thienyl, thiazolyl, or pyridyl;
  • Ar 2 is (C 5 -C 7 )cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl, triazolyl or pyrazolyl;
  • R 1 is chloro, fluoro, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy, said (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
  • R 1 and R 3 are each independently, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro.
  • a group of compounds which is preferred among the T2 group of compounds, designated the U2 Group, contains those compounds wherein
  • M is —Ar 1 —Ar 2 ,
  • Ar 1 is phenyl
  • Ar 2 is (C 5 -C 7 )cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl, said Ar 2 optionally mono- or di-substituted independently with R 1 or R 2 ;
  • R 1 is chloro, fluoro, methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy;
  • R 2 is methoxy, chloro or fluoro.
  • a group of compounds which is preferred among the T2 group of compounds, designated the V2 Group, contains those compounds wherein
  • M is —Ar 1 —Ar 2 ,
  • Ar 1 is phenyl
  • Ar 2 is (C 5 -C 7 )cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl, said Ar 2 optionally mono- or di-substituted independently with R 1 or R 2 ;
  • R 1 is chloro, fluoro, methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy;
  • R 2 is methoxy, chloro or fluoro.
  • An especially preferred compound of the U2 Group of compounds is a compound wherein
  • A is methylsulfonyl
  • Z is carboxyl
  • M is 4-(cyclohexyl)phenyl.
  • An especially preferred compound of the U2 Group of compounds is a compound wherein
  • A is methylsulfonyl
  • Z is carboxyl
  • M is 4-(thiazol-2-yl)phenyl.
  • An especially preferred compound of the U2 Group of compounds is a compound wherein
  • A is methylsulfonyl
  • Z is carboxyl
  • M is 4-(pyrazin-2-yl)phenyl.
  • a preferred group of compounds designated the W2 Group, contains those compounds having the Formula I as shown above wherein
  • A is (C 1 -C 3 )alkylsulfonyl
  • Q is -(C 2 -C 4 )alkylene-X-;
  • X is thiazolyl or furanyl; said thiazolyl or furanyl optionally mono- or di-substituted independently with methyl, methoxy, fluoro, chloro, trifluoromethyl, difluoromethoxy or trifluoromethoxy;
  • K is oxy-ethylene or propylene, said propylene optionally being mono-unsaturated
  • M is —Ar, said —Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, pyrimidyl, imidazolyl, cyclohexyl, cyclopentyl, cyclobutyl, or cycloheptyl;
  • R 1 is halo, (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, said (C 1 -C 6 )alkoxy, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkanoyl or (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and
  • R 2 and R 3 are each independently methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro.
  • a group of compounds which is preferred among the W2 group of compounds, designated the X2 Group, contains those compounds wherein
  • A is methylsulfonyl
  • Z is carboxyl, or (C 1 -C 4 )alkoxycarbonyl
  • X is thiazolyl
  • K is oxy-ethylene or propylene
  • M is phenyl optionally mono- or di-substituted independently with fluoro, chloro, methoxy, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
  • An especially preferred compound of the X2 Group of compounds is a compound wherein
  • Z is carboxyl
  • K is propylene
  • M is 3-(chloro)phenyl.
  • An especially preferred compound of the X2 Group of compounds is a compound wherein
  • Z is carboxyl
  • K is oxy-ethylene
  • M is 3,5-dichlorophenyl.
  • Another aspect of this invention is directed to a compound of Formula IA
  • A is (C 1 -C 6 )alkylsulfonyl, (C 3 -C 7 )cycloalkylsulfonyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkylsulfonyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy, (C 1 -C 4 )alkyl or halo;
  • W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N-(C 1 -C 4 )alkyleneaminosulfonyl-, sulfonylamino, N-(C 1 -C 4 )alkylenesulfonylamino, carboxamido, N-(C 1 -C 4 )alkylenecarboxamido, carboxamidooxy, N-(C 1 -C 4 )alkylenecarboxamidooxy, carbamoyl, -mono-N-(C 1 -C 4 )alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C 1 -C 4 )alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
  • X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C 1 -C 3 )alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C 1 -C 4 )alkoxy, or carbamoyl;
  • Z is carboxyl, (C 1 -C 6 )alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C 1 -C 4 )alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
  • K is a bond, (C 1 -C 8 )alkylene, thio(C 1 -C 4 )alkylene or oxy(C 1 -C 4 )alkylene, said (C 1 -C 8 )alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
  • M is —Ar, —Ar 1 —V—Ar 2 , —Ar 1 —S—Ar 2 , —Ar 1 —O—Ar 2 , —Ar 1 —S—(C 1 -C 3 )—Ar 2 —, —Ar 1 —(C 1 -C 3 )—S—Ar 2 — or —Ar 1 —(C 1 -C 3 )—S—(C 1 -C 3 )—Ar 2 , wherein Ar, Ar 1 and Ar 2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • Ar, Ar 1 and Ar 2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon, nitrogen or sulfur with up to three substituents independently selected from R 1 , R 2 and R 3 wherein R 1 , R 2 and R 3 are oxo, hydroxy, nitro, halo, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, (C 1 -C 7 )cycloalkyl(C 1 -C 4 )alkanoyl, formyl, (C 1 -C 8 )alkanoyl, (
  • R 1 , R 2 and R 3 are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy;
  • V is a bond or (C 1 -C 3 )alkylene optionally mono-unsaturated and optionally mono- or di-substituted independently with hydroxy or fluoro,
  • A is (C 1 -C 6 )alkanoyl, or (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkanoyl, said A moieties optionally mono-, di- or tri-substituted independently on carbon with hydroxy or halo;
  • W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N-(C 1 -C 4 )alkyleneaminosulfonyl-, sulfonylamino, N-(C 1 -C 4 )alkylenesulfonylamino, carboxamido, N-(C 1 -C 4 )alkylenecarboxamido, carboxamidooxy, N-(C 1 -C 4 )alkylenecarboxamidooxy, carbamoyl, -mono-N-(C 1 -C 4 )alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C 1 -C 4 )alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
  • X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C 1 -C 3 )alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C 1 -C 4 )alkoxy, or carbamoyl;
  • Z is carboxyl, (C 1 -C 6 )alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C 1 -C 4 )alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
  • K is (C 1 -C 8 )alkylene, thio(C 1 -C 4 )alkylene or oxy(C 1 -C 4 )alkylene, said (C 1 -C 8 )alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
  • M is —Ar, —Ar 1 —V—Ar 2 , —Ar 1 —S—Ar 2 , —Ar 1 —O—Ar 2 , —Ar 1 —S—(C 1 -C 3 )—Ar 2 —, —Ar 1 —(C 1 -C 3 )—S—Ar 2 — or —Ar 1 —(C 1 -C 3 )—S—(C 1 -C 3 )—Ar 1 wherein Ar, Ar 1 and Ar 2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
  • Ar, Ar 1 and A 2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon, nitrogen or sulfur ith up to three substituents independently selected from R 1 , R 2 and R 3 wherein R 1 , R 2 and R 3 are oxo, H, hydroxy, nitro, halo, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alktl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkanoyl, formyl, (C 1 -C 8 )alkano
  • R 1 , R 2 and R 3 are optionally mono-, di- or tri-substituted independently on carbon with halo or hydroxy;
  • V is a bond or (C 1 -C 3 )alkylene optionally mono-unsaturated and optionally mono- or di-substituted independently with hydroxy or fluoro
  • Yet another aspect of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • Yet another aspect of this invention is directed to a method for treating a mammal having a condition which presents with low bone mass comprising administering to said mammal
  • Yet another aspect of this invention is directed to a kit comprising
  • container means for containing said first and second dosage forms.
  • Yet another aspect of this invention is directed to a method for treating a mammal in need of kidney regeneration comprising administering to said mammal a therapeutically effective amount of a compound of Formula 1A or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a method for treating a mammal having a condition which presents with low bone mass comprising administering to said mammal a therapeutically effective amount of a compound of Formula IA or a pharmaceutically acceptable salt or prodrug thereof.
  • Yet another aspect of this invention is directed to a pharmaceutical composition which comprises a therapeutically effective amount of a compound of Formula IA or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • Yet another aspect of this invention is directed to a method for lowering intraocular pressure in a mammal comprising administering a therapeutically effective amount of a compound of Formula IA or a pharamaceutically acceptable salt or prodrug thereof to a mammal in need.
  • condition(s) which presents with low bone mass refers to a condition where the level of bone mass is below the age specific normal as defined in standards by the World Health Organization “Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a World Health Organization Study Group. World Health Organization Technical Series 843”. Included in “condition(s) which presents with low bone mass” are primary and secondary osteoporosis. Secondary osteoporosis includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis and immunosuppressive-induced osteoporosis.
  • condition(s) which presents with low bone mass also includes long term complications of osteoporosis such as curvature of the spine, loss of height and prosthetic surgery.
  • condition which presents with low bone mass also refers to a mammal known to have a significantly higher than average chance of developing such diseases as are described above including osteoporosis (e.g., post-menopausal women, men over the age of 60).
  • osteoporosis e.g., post-menopausal women, men over the age of 60.
  • bone mass augmenting or enhancing uses include increasing the bone fracture healing rate, enhancing the rate of successful bone grafts, bone healing following facial reconstruction or maxillary reconstruction or mandibular reconstruction, prosthetic ingrowth, vertebral synostosis or long bone extension.
  • bone mass actually refers to bone mass per unit area which is sometimes (although not strictly correctly) referred to as bone mineral density.
  • treating includes preventative (e.g., prophylactic) and palliative treatment.
  • pharmaceutically acceptable it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • prodrug refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
  • exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the Formula I compounds include but are not limited to substituents wherein the Z moiety is independently carboxyl and the free hydrogen is replaced by (C 1 -C 4 )alkyl, (C 2 -C 7 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbon
  • Exemplary five to six membered aromatic rings optionally having one or two heteroatoms selected independently from oxygen, nitrogen and sulfur are phenyl, furyl, thienyl, pyrrolyi, oxazolyl, thiazolyi, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyi, pyridinyl, pyridiazinyl, pyrimidinyl and pyrazinyl.
  • Exemplary partially saturated, fully saturated or fully unsaturated five to eight membered rings optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen (i.e., Ar, Ar 1 and Ar 2 ) are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl.
  • FIG. 1 Further exemplary five membered rings are furyl, thienyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-trizaolyl
  • FIG. 1 For exemplary six membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-trizainyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 2H-1,2-oxaziny
  • FIG. 1 Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cydooctadienyl.
  • Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen are indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, 4Hquinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
  • alkylene saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons.
  • alkylene groups are methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene).
  • halo is meant chloro, bromo, iodo, or fluoro.
  • alkyl straight chain saturated hydrocarbon or branched saturated hydrocarbon.
  • alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
  • alkoxy straight chain saturated alkyl or branched saturated alkyl bonded through an oxy.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy.
  • the term mono-N- or di-N,N-(C 1 -C x )alkyl . . . refers to the (C 1 -C x )alkyl moiety taken independently when it is di-N,N-(C 1 -C x )alkyl . . . (x refers to integers).
  • M moieties defined above are optionally substituted (e.g., the mere listing of a substituent such as R 1 in a subgenus or dependent claim does not mean that M is always substituted with the R 1 moiety unless it is stated that the M moiety is substituted with R 1 ).
  • a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate, through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom.
  • pyridyl means 2-, 3-, or 4-pyridyl
  • thienyl means 2-, or 3-thienyl, and so forth.
  • pharmaceutically-acceptable salt refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene-sulfonate.
  • anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene-sulfonate.
  • nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,N′-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, megiamine (N-methyl-glucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
  • nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,N′-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, megiamine (N-methyl-glucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propan
  • reaction-inert solvent and “inert solvent” refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
  • the parenthetical negative or positive sign used herein in the nomenclature denotes the direction plane polarized light is rotated by the particular stereoisomer.
  • DTT means dithiothreitol.
  • DMSO means dimethyl sulfoxide.
  • EDTA means ethylenediamine tetraacetic acid.
  • the methods and compounds of this invention result in bone formation resulting in decreased fracture rates.
  • This invention makes a significant contribution to the art by providing compounds and methods that increase bone formation resulting in prevention, retardation, and/or regression of osteoporosis and related bone disorders.
  • the compounds of this invention can be made by processes which include processes known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes may be described in the experimental section.
  • substituents e.g., carboxyl
  • carboxyl examples are hydroxyl or carboxaldehyde
  • the Formula I compounds wherein B is nitrogen can be prepared by sequential alkylation of sulfonamide or amide with two appropriate alkyl halides or alkylsulfonates; or reductive amination of an amine containing the necessary acidic functionality (suitably protected) with an aldehyde followed by reaction with an acylating agent or a sulfonyl chloride followed by hydrolysis.
  • the compounds of Formula I can be prepared according to the methods described in SCHEMES 1 and 2 below.
  • the sequences involve sequential alkylation of the appropriate formula 1 sulfonamide or amide with two appropriate alkyl halides or alkylsulfonates.
  • SCHEMES 1 and 2 merely differ in the order of addition of the two alkylating agents.
  • the alkylation order is typically chosen depending on the reactivity of the electrophilic side-chain. In order to reduce the amount of dialkylation which occurs in the first alkylation step, the less reactive electrophilic side-chain is typically introduced first.
  • One of the alkylating agents typically contains a carboxylic acid or acid isostere suitably masked with an appropriate protecting group.
  • the formula 3 acid precursor is a carboxylic ester where R represents either a straight chain lower alkyl, preferably methyl or ethyl, or a teit-butyl or phenyl group.
  • R represents either a straight chain lower alkyl, preferably methyl or ethyl, or a teit-butyl or phenyl group.
  • Other acid isosteres can be employed by appropriately modifying these SCHEMES using methods known to those skilled in the art (see SCHEME 6 which describes a tetrazol preparation for an example).
  • Typical alkylating agents are primary, secondary, benzylic or allylic and are preferably alkyl bromides or alkyl iodides.
  • the formula 1 sulfonamide or amide is converted to its anion with a strong base such as sodium hydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium tert-butoxide, etc. in an aprotic solvent such as dimethylformamide, tetrahydrofuran (THF) or dimethylformamide/benzene at a temperature of about ⁇ 78° C. to about 100° C.
  • THF tetrahydrofuran
  • the resulting anion is alkylated with the appropriate formula 2 or 3 alkyl halide or alkyl sulfonate (wherein X′ is the halide or sulfonate) at a temperature of about 0° C.
  • the formula 4 or 5 compounds are converted to the anion again using a suitable base such as sodium hydride, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, potassium tert-butoxide, or potassium carbonate in an aprotic solvent such as dimethylformamide, THF, dimethylformamidelbenzene, or acetone at a temperature of about ⁇ 78° C. to about 100° C.
  • a suitable base such as sodium hydride, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, potassium tert-butoxide, or potassium carbonate
  • an aprotic solvent such as dimethylformamide, THF, dimethylformamidelbenzene, or acetone
  • the formula 6 ester is hydrolyzed to the corresponding Formula I acid (in cases where R represents methyl or ethyl) with a dilute aqueous basic solution (preferably sodium or potassium hydroxide in aqueous methanol or ethanol), lithium hydroxide in aqueous alcoholic solvent, aqueous tetrahydrofuran at a temperature of about 0° C. to about 80° C., or by using methods described in “Protecting Groups in Organic Synthesis,” Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc., 1991.
  • a dilute aqueous basic solution preferably sodium or potassium hydroxide in aqueous methanol or ethanol
  • lithium hydroxide in aqueous alcoholic solvent aqueous tetrahydrofuran at a temperature of about 0° C. to about 80° C.
  • Formula I compounds can also be prepared from amines (see SCHEMES 3-4 for examples).
  • the appropriate amine starting materials can be commercially obtained or can be prepared using methods known to those skilled in the art (see “The Chemistry of Amino, Nitroso and Nitro Compounds and their Derivatives,” Ed. S. Patai, J. Wiley, New York, 1982).
  • the amine starting materials may be prepared from the corresponding formula 7 or 8 nitrites.
  • Nitriles are either available from commercial sources or can be prepared using methods known to those skilled in the art (see Rappaport, “The Chemistry of the Cyano Group,” Interscience, New York, 1970 or Patai and Rappaport, “The Chemistry of Functional Groups,” pt. 2, Wiley, New York, 1983).
  • the formula 7 or 8 nitrile is reduced with a reducing agent such as borane-tetrahydrofuran complex, borane-methyl sulfide complex, lithium aluminum hydride, or hydrogenation in the presence of Raney nickel or a platinum or palladium catalyst in a protic solvent such as methanol or ethanol at a temperature of about 0° C. to about 50° C.
  • a reducing agent such as borane-tetrahydrofuran complex, borane-methyl sulfide complex, lithium aluminum hydride, or hydrogenation in the presence of Raney nickel or a platinum or palladium catalyst in a protic solvent such as methanol or ethanol at
  • the resulting formula 9 or 10 amine is converted to either the formula 11 or 12 sulfonamide or amide by treatment (acylation) with an acid chloride or sulfonyl chloride in the presence of a weak base such as triethylamine, pyridine, or 4-methylmorpholine in an aprotic solvent such as methylene chloride or diethyl ether at a temperature of about ⁇ 20° C. to about 50° C.
  • a weak base such as triethylamine, pyridine, or 4-methylmorpholine
  • an aprotic solvent such as methylene chloride or diethyl ether
  • coupling of amines of formulas 9 or 10 with carboxylic acids are conveniently carried out in an inert solvent such as dichloromethane or N,N-dimethylformamide (DMF) by a coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or 1,3-dicyclohexylcarbodiimide (DCC) in the presence of 1-hydroxybenzotriazole hydrate (HOBT) to generate compounds of formula 11 or 12.
  • EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DCC 1,3-dicyclohexylcarbodiimide
  • HOBT 1-hydroxybenzotriazole hydrate
  • the coupling can be effected with a coupling reagent such as benzotriazol-1-yloxy-ris(dimethylamino)-phosphonium hexafluorophosphate (BOP) in an inert solvent such as methanol.
  • a coupling reagent such as benzotriazol-1-yloxy-ris(dimethylamino)-phosphonium hexafluorophosphate (BOP) in an inert solvent such as methanol.
  • BOP benzotriazol-1-yloxy-ris(dimethylamino)-phosphonium hexafluorophosphate
  • an inert solvent such as methanol
  • the formula 9 and 10 amines may also be prepared via reduction of formula 15 and 16 amides.
  • the reduction can be achieved using reagents such as a borane-tetrahydrofuran complex, a borane-methyl sulfide complex, or diisobutyaluminum hydride in an aprotic solvent such as tetrahydrofuran or diethyl ether at a temperature of about ⁇ 78° C. to about 60° C.
  • the formula 9 and 10 amines can also be obtained from the corresponding nitro precursors by reduction of the nitro group using reducing reagents such as zinc/HCl, hydrogenation in the presence of Raney nickel, palladium, or platinum catalysts, and other reagents as described by P. N. Rylander in “Hydrogenation Methods,” Academic Press, New York, 1985.
  • the reductive amination is typically carried out with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride preferably at a pH of between 6 and 8.
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride preferably at a pH of between 6 and 8.
  • the reaction is normally performed in a protic solvent such as methanol or ethanol at temperatures of about ⁇ 78° C. to about 40° C. (for a leading reference see A. Abdel-Magid, C. Maryanoff, K. Carson, Tetrahedron Lett. 39, 31, 5595-5598, 1990).
  • Other conditions involve the use of titanium isopropoxide and sodium cyanoborohydride (R. J. Mattson et al, J. Org. Chem. 1990, 55, 2552-4) or preformation of the imine under dehydrating conditions followed by reduction.
  • the resulting formula 42, 42A amine is transformed to the desired sulfonamide or amide by coupling with an acid chloride, sulfonyl chloride, or carboxylic acid as described in SCHEMES 3 and 4. If desired, hydrolysis provides the corresponding acid.
  • the alkylation is achieved by treatment of the formula 59 compound with a base such as sodium hydride, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium tert-butoxide, or potassium carbonate in an aprotic solvent such as dimethylformamide, dimethylformamide/benzene, or acetone.
  • a base such as sodium hydride, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium tert-butoxide, or potassium carbonate
  • an aprotic solvent such as dimethylformamide, dimethylformamide/benzene, or acetone.
  • Alkylation occurs at a temperature of about ⁇ 78° C. to about 100° C.
  • Preferred conditions for converting the resulting nitrile to the formula 60 tetrazole involve treatment with dibutyltin oxide and trimethylsilylazide, in toluene at reflux (S. J. Wittenberger and B. G. Don
  • Formula 46 esters can be prepared using the procedures described earlier (see SCHEMES 1 and 2). Subsequent Heck coupling of this intermediate to an arylhalide (preferably an aryl bromide or aryl iodide), an aryl triflate, or a ring system which contains a vinyl bromide, iodide, or trifiate is accomplished with a palladium catalyst, such as palladium acetate or tetrakis(triphenylphosphine)palladium(0) in the presence of a trialkylamine, such as triethyla mine, In some cases, a triarylphosphine may be added to the reaction.
  • a palladium catalyst such as palladium acetate or tetrakis(triphenylphosphine)palladium(0) in the presence of a trialkylamine, such as triethyla mine.
  • a triarylphosphine may be added to the reaction.
  • the reaction is typically performed in an aprotic solvent such as dimethylformamide or acetonitrile at a temperature of about 0° C. to about 150° C. (see R. F. Heck in Comp. Org. Syn., Vol. 4, Ch. 4.3, p. 833 or Daves and Hallberg, Chem. Rev. 1989, 89,1433).
  • formula 47 compounds can be hydrolyzed to the corresponding acid.
  • the formula 47 compounds can be hydrogenated and, if desired, further hydrolyzed to the corresponding formula 49 acid.
  • Preferred conditions for hydrogenation involve the use of a palladium or platinum catalyst in an alcoholic solvent such as ethanol or methanol at a temperature of about 0° C. to about 50° C. In cases where M represents a partially saturated ring system, hydrogenation will generate a saturated ring system.
  • Formula 51 compounds can be prepared as described in SCHEMES 1 and 2 by alkylation of formula 5 compounds with an electrophile of formula 2 which contains the appropriate functionality on the ring M, for subsequent conversion to an aldehyde.
  • an electrophile of formula 2 which contains the appropriate functionality on the ring M
  • effectrophiles of formula 2 could contain a protected alcohol on the ring, M, which, after alkylation, can be deprotected and oxidized to the aldehyde, using reagents known to those skilled in the art, to generate formula 51 compounds.
  • An alternative method is to alkylate with an electrophile of formula 2 where M contains a vinyl group.
  • oxidative cleavage of the double bond provides the desired formula 51 aldehyde.
  • the oxidative cleavage can be accomplished by transforming the double bond to the 1,2-diol with catalytic osmium tetroxide and N-methylmorpholine followed by oxidative cleavage to the aldehyde using sodium periodate.
  • oxidative cleavage via ozonolysis followed by reduction using reagents such as methyl sulfide, triphenylphosphine, zinc/acetic acid, or thiourea, will generate the desired formula 51 aldehyde.
  • LMetal represents any organometallic reagent such as an organolithium or Grignard reagent in an aprotic solvent such as diethyl ether or tetrahydrofuran at a temperature of about ⁇ 78° C. to about 80° C., followed by hydrolysis of the ester as described above, provides the desired formula 50 compound.
  • organometallic reagent such as an organolithium or Grignard reagent
  • an aprotic solvent such as diethyl ether or tetrahydrofuran
  • the coupling reaction is achieved using about two equivalents of a base, such as sodium carbonate, potassium carbonate, sodium hydroxide, thallium hydroxide, potassium phosphate, or sodium methoxide, in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), palladium acetate, palladium chloride, tris(dibenzylideneacetone)dipalladium(0) or [1,4-bis(diphenylphosphine)butane]palladium(0).
  • a base such as sodium carbonate, potassium carbonate, sodium hydroxide, thallium hydroxide, potassium phosphate, or sodium methoxide
  • a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), palladium acetate, palladium chloride, tris(dibenzylideneacetone)dipalladium(0) or [1,4-bis(diphenylpho
  • the reaction may be run in aqueous alcoholic solvents (methanol or ethanol), aqueous tetrahydrofuran, aqueous acetone, aqueous glycol dimethyl ether, or aqueous benzene at temperatures ranging from about 0° C. to about 120° C.
  • aqueous alcoholic solvents methanol or ethanol
  • aqueous tetrahydrofuran aqueous acetone
  • aqueous glycol dimethyl ether aqueous glycol dimethyl ether
  • aqueous benzene at temperatures ranging from about 0° C. to about 120° C.
  • Ar 1 represents a partially saturated ring
  • reduction of the ring to provide a saturated ring system may be performed at this point.
  • Conditions to accomplish this transformation involve hydrogenation in the presence of a catalyst such as palladium or platinum in an alcoholic solvent (ethanol or methanol) and/or ethyl acetate.
  • Formula 54 compounds which contain an aldehyde functional group can be prepared using methods described in SCHEMES 8 and 9.
  • an appropriate organometallic reagent such as an organolithium or Grignard reagent
  • an aprotic solvent such as diethyl ether or tetrahydrofuran at a temperature of about ⁇ 78° C. to about 80° C.
  • formula 56 compounds wherein B is N and A, Q and K are as described in the Summary and Ar 1 and Ar 2 are as described in SCHEME 9).
  • reduction of the aidehyde followed by hydrolysis provides formula 55 compounds.
  • the coupling is achieved by addition of a coupling agent such as triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate in inert solvents such as methylene chloride or tetrahydrofuran at a temperature of about 0° C. to about 80° C. If desired, subsequent hydrolysis yields the corresponding acid.
  • a coupling agent such as triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate in inert solvents such as methylene chloride or tetrahydrofuran
  • formula 106 compounds wherein B is N and A, K, and M are as described in the Summary and R is as described in SCHEMES 1 and 2 and accordingly, the corresponding acids is described in SCHEME 12.
  • a formula 102 compound is added to a formula 105 compound (wherein the X is an aromatic ring such as a benzene ring or a thiophene ring) in the presence of a Lewis acid such as titanium tetrachloride or a mineral acid such as hydrochloric acid.
  • a Lewis acid such as titanium tetrachloride or a mineral acid such as hydrochloric acid.
  • the formula 106 ester can be converted to the corresponding acid by hydrolysis or deprotection.
  • Formula 104 chloromethyl compounds are treated with the appropriate substituted aromatic ring system, M, such as 4-ethoxybenzene or thiophene in the presence of a Lewis acid such as titanium tetrachloride or a mineral acid such as hydrochloric acid in an aprotic solvent such as chloroform at a temperature of about 0° C. to about 80° C. to yield the formula 107 compound which may subsequently be hydrolyzed or deprotected as described above to yield the corresponding acid.
  • M such as 4-ethoxybenzene or thiophene
  • formula 104 chloromethyl compounds can be treated with a Lewis acid such as titanium tetrachloride and an appropriately substituted vinyl silane in an aprofic solvent such as methylene chloride at a temperature of about ⁇ 50° C. to about 50° C. to give formula 108 compounds which may subsequently be hydrolyzed or deprotected as described above to yield the corresponding acid.
  • a Lewis acid such as titanium tetrachloride and an appropriately substituted vinyl silane in an aprofic solvent such as methylene chloride
  • Formula 109 compounds wherein B is N and A, Q, R and M are as described above, and accordingly, the corresponding acids
  • SCHEME 14 Another method of preparing certain Formula I compounds (i.e., formula 109 compounds, wherein B is N and A, Q, R and M are as described above, and accordingly, the corresponding acids) is described in SCHEME 14.
  • Formula 104 chloromethyl compounds are treated with a Lewis acid such as titanium tetrachioride and an appropriately substituted allyl silane in an aprotic solvent such as chloroform at a temperature of about 0° C. to about 80° C. to give formula 109 compounds which may subsequently be hydrolyzed or deprotected as described above.
  • Formula 112 compounds wherein B is N and A, Q, R and M are as described above, and accordingly, the corresponding acids
  • SCHEME 15 Scheme 104 chloromethyl compounds are treated with a formula 111 sulfinic acid in the presence of a base such as triethylamine in an aprotic solvent such as chloroform at a temperature of about ⁇ 30° C. to about 50° C. to give formula 112 compounds which may subsequently be hydrolyzed or deprotected as described above to yield the corresponding acid.
  • a base such as triethylamine
  • aprotic solvent such as chloroform
  • Formula I compounds (wherein B is C(H) and Q, M and K are as described in the Summary, R′ is a small chain alkyl group, and R 1 represents the alkyl groups on A as described in the Summary) can be prepared according to SCHEME 16.
  • Formula 113 beta-ketoesters are alkylated sequentially with formula 114 compounds followed by alkylation of formula 116 compounds to give formula 117 compounds (J. Med. Chem. 26, 1993, p335-41).
  • Alkylations can be carried out in a suitable solvent such as DMF, THF, ether, or benzene using an appropriate base such as sodium hydride, LDA, or potassium carbonate at a temperature of about ⁇ 78° C. to about 80° C.
  • the resulting formula 117 disubstituted keto esters are hydrolyzed and decarboxylated to give the corresponding formula 118 compound by using an aqueous base such as sodium hydroxide to hydrolyze the ester, followed by an acidic quench such as aqueous hydrochloric acid to effect decarboxylation.
  • an aqueous base such as sodium hydroxide to hydrolyze the ester
  • an acidic quench such as aqueous hydrochloric acid to effect decarboxylation.
  • Forrnula I compounds (wherein B is C(H) and Q, M and K are as described in the Summary, R′ is as described above, and R 1 represents the aikyl groups on A as described in the Summary) may be prepared according to SCHEME 17. Sequential alkylation of a malonate derivative of formula 119 provides the formula 121 dialkylated species. Deprotection of the ester group by treatment with a strong acid such as TFA or HCl in ethanol at a temperature of about ⁇ 20° C. to about 50° C. leads to the formula 122 decarboxylated product.
  • a strong acid such as TFA or HCl in ethanol
  • Conversion of the acid to an acid chloride using thionyl chloride or oxalyl chloride in an aprotic solvent at a temperature of about ⁇ 78° C. to about 50° C. or to a Weinreb amide using methoxymethyl amine in the presence of a suitable coupling agent such as DCC or DEC in an aprotic solvent at a temperature of about ⁇ 30° C. to about 50° C. provides formula 123 compounds.
  • Formula 123 are suitable substrates for addition of various organometallic species (e.g., grignard reagents, organo-cadmium reagents) which after hydrolysis of the terminal ester provide the keto-acid compounds of formula 118.
  • formula 118 compounds can be prepared using methods described previously (e.g. see SCHEMES 7, 8, 9, 10, and 11) where one or both of the side chains are further functionalized after attachment.
  • Certain amides or sulfonamides described by formulas 21, 22, and 23 (wherein W and Z are as described in the Summary and X and M are aromatic or saturated ring systems may be prepared according to SCHEME 18.
  • Formula 25, 26 and 27 alkynyl amides or sulfonamides are prepared by coupling a formula 24 alkynyl sulfonamide or amide to an aromatic or vinyl halide, preferably an aromatic or vinyl bromide or iodide (wherein W and Z are as defined above and where X and M represent an aromatic ring or a partially saturated ring system).
  • the coupling is typically accomplished in the presence of copper iodide, a palladium catalyst, such as palladium chloride, bis(triphenylphosphine)palladium dichloride, or tetrakis(triphenylphosphine)palladium(0), and an amine such as triethylamine, diisopropylamine, or butylamine in an aprotic solvent such as acetonitrile at a temperature of about 0° C. to about 100° C.
  • a palladium catalyst such as palladium chloride, bis(triphenylphosphine)palladium dichloride, or tetrakis(triphenylphosphine)palladium(0)
  • an amine such as triethylamine, diisopropylamine, or butylamine in an aprotic solvent such as acetonitrile at a temperature of about 0° C. to about 100° C.
  • the resulting formula 25, 26 and 27 alkynes can be converted to the corresponding formula 21, 22 or 23 alkanes, via hydrogenation in the presence of a palladium or platinum catalyst and in solvents such as methanol, ethanol, and/or ethyl acetate at a temperature of about 0° C. to about 50° C.
  • a palladium or platinum catalyst such as methanol, ethanol, and/or ethyl acetate
  • solvents such as methanol, ethanol, and/or ethyl acetate
  • Pd—CaCO 3 —PbO Lindlar catalyst
  • M represents a partially saturated ring system
  • hydrogenation will convert M to a fully saturated ring system.
  • Alkylation and deprotection as described in SCHEMES 1 and 2 affords the corresponding Formula I compounds.
  • formula 33 compounds (wherein A and X are as described in the Summary) can be prepared from a suitable formula 32 amine (e.g., methoxyarylalkylamine).
  • Formula 32 amines are commercially available or can be prepared by methods known to those skilled in the art (for example, see SCHEME 4) and are converted to formula 31 sulfonamides or amides using methods, for example, described in SCHEME 3 and 4.
  • the resulting formula 31 aromatic methyl ether is deprotected with reagents such as boron tribromide, pyridinium hydrochloride, hydrogen bromide/acetic acid, or other reagents as described in Protecting Groups in Organic Synthesis, Second Edition, T. W. Greene and P.
  • N-bromosuccinimide N-bromosuccinimide
  • a radical initiator such as AIBN or a peroxide, preferably benzoyl peroxide.
  • the reaction can be initiated with light.
  • the reaction is done in an inert solvent such as carbon tetrachloride or chloroform at a temperature of about 50° C. to about 100° C.
  • SCHEME 21 demonstrates the synthesis of alkylating agents useful for preparing Formula I compounds where M represents a biaryl or aryl cyclic group.
  • Suzuki-type coupling of an aryl iodide or bromide or a ring system containing a vinyl bromide or iodide (Ar 2 ) with a methylaryl boronic acid (Ar 1 ) using the conditions described in SCHEME 9 provides formula 34 compounds.
  • formula 34 compounds can be reduced to generate a fully saturated ring.
  • the reduction is accomplished by hydrogenation in the presence of palladium or platinum catalysts typically in protic solvents (methanol or ethanol), tetrahydrofuran, or ethyl acetate.
  • Halogenation of the methyl group using reagents and conditions as described in SCHEME 20 provides formula 35 alkylafing agents.
  • Alcohols are obtained from commercial sources or can be prepared using methods known to those skilled in the art. For example, in SCHEME 22, a carboxylic acid or ester is reduced to the alcohol using reagents such as sodium borohydride, lithium aluminum hydride, borane-tetrahydrofuran complex, borane-methyl sulfide complex, etc.
  • reagents such as sodium borohydride, lithium aluminum hydride, borane-tetrahydrofuran complex, borane-methyl sulfide complex, etc.
  • the corresponding alkyl chlorides are typically prepared from the alcohols with reagents such as hydrogen chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or triphenylphosphine/carbon tetrachloride.
  • alkyl bromides For the preparation of alkyl bromides, the alcohol is commonly treated with reagents such as hydrogen bromide, phosphorous tribromide, triphenylphosphine/bromine, or carbonyldiimidazole/allyl bromide (Kamijo, T., Harada, H., lizuka, K. Chem. Pharm. Bull. 1983, 38, 4189).
  • reagents such as triphenylphosphine/iodine/imidazole or hydogen iodide.
  • Alkyl chlorides can be converted to the more reactive alkyl bromides or alkyl iodides by treatment with an inorganic salt such as sodium bromide, lithium bromide, sodium iodide, or potassium iodide in solvents such as acetone or methyl ethyl ketone.
  • Alkyl sulfonates can also be used as electrophiles or can be converted to alkyl halides. Sulfonates are prepared from the alcohol using a mild base such as triethylamine or pyridine and a sulfonyl chloride in an inert solvent such a methylene chloride or diethyl ether.
  • Conversion to the halide is accomplished by treatment with an inorganic halide (sodium iodide, sodium bromide, potassium iodide, potassium bromide, lithium chloride, lithium bromide, etc) or a tetrabutylammonium halide.
  • an inorganic halide sodium iodide, sodium bromide, potassium iodide, potassium bromide, lithium chloride, lithium bromide, etc
  • a tetrabutylammonium halide sodium iodide, sodium bromide, potassium iodide, potassium bromide, lithium chloride, lithium bromide, etc
  • Cinnamic acids or esters are commonly available from commercial sources and can by converted to formula 37 or 38 alkylating agents as follows (see SCHEME 23).
  • the cinnamic acid or ester derivatives are reduced by hydrogenation in the presence of palladium or platinum catalysts typically in protic solvents (e.g., methanol or ethanol), tetrahydrofuran, or ethyl acetate.
  • protic solvents e.g., methanol or ethanol
  • Reduction and conversion to the alkyl halide or sulfonate as described in SCHEME 22 provides formula 38.
  • the cinnamic acids or esters are converted directly to formula 39 alcohols by treatment with reagents such as lithium aluminum hydride in inert solvents such as tetrahydrofuran and diethyl ether.
  • reagents such as lithium aluminum hydride in inert solvents such as tetrahydrofuran and diethyl ether.
  • the cinnamic acid or ester can be reduced to the formula 40 allylic alcohol using reagents such as lithium aluminum hydride/aluminum chloride, diisobutylaluminum hydride, or lithium borohydride. Conversion to the allylic halide or sulfonate as described in SCHEME 22 provides formula 37 reagents.
  • formula 41 alkylating agents (wherein W and M are as described in the Summary above) are described in SCHEME 24.
  • Formula 42 compounds are alkylated with a variety of bases the choice of which is dependent on the nature of W and M.
  • Some preferred bases are sodium hydroxide, sodium hydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and potassium tert-butoxide, etc.
  • Treatment of the resulting anion with a variety of dialkylhalides generates the desired formula 41. alkylating agents.
  • the preferred conditions involve formation of the alkoxide anion with sodium hydroxide followed by addition of a dihaloalkane, e.g. dibromoalkane.
  • the reaction is normally performed in water at about 75° C. to about 125° C.
  • Aldehydes useful for the chemistry described in SCHEME 5 are available from commercial sources or can be prepared from available intermediates using methods known to those skilled in the art.
  • SCHEME 25 demonstrates an exemplary method used to prepare formula 43 hydroxy aldehydes (where M in SCHEME 5 contains a hydroxy substituted alkyl group).
  • a dialdehyde where one of the aldehydes is protected as a formula 44 acetal (wherein the OR groups are conventional substituents used in an acetal protecting group)
  • an organometallic reagent preferably an organolithium or Grignard reagent, in an inert solvent such as tetrahydrofuran or diethyl ether, provides formula 45 compounds.
  • organometallic reagent preferably an organolithium or Grignard reagent
  • Intermediate chloromethyl compounds can be prepared as described in SCHEMES 26 and 27.
  • the appropriate formula 101 or 103 sulfonamide or carboxamide is treated with a formaldehyde equivalent such as paraformaldehyde in an inert organic solvent such as methylene chloride or chloroform with a suitable catalyst such as HCl, zinc chloride or trimethylsilyl chloride at temperatures ranging from about 0° C. to about 60° C. to give the formula 102 and 104 chloromethyl derivatives, respectively.
  • a formaldehyde equivalent such as paraformaldehyde
  • an inert organic solvent such as methylene chloride or chloroform
  • a suitable catalyst such as HCl, zinc chloride or trimethylsilyl chloride
  • anti-resorptive agents for example progestins polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists, estrogen, estrogeniprogestin combinations, Premarin, estrone, estriol or 17 ⁇ - or 17 ⁇ -ethynyl estradiol
  • anti-resorptive agents for example progestins polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists, estrogen, estrogeniprogestin combinations, Premarin, estrone, estriol or 17 ⁇ - or 17 ⁇ -ethynyl estradiol
  • progestins are available from commercial sources and include: algestone acetophenide, altrenogest, amadinone acetate, anagestone acetate, chlormadinone acetate, cingestol, clogestone acetate, clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone, dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel, flurogestone acetate, gestaclone, gestodene, gestonorone caproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, melengestrol acetate, methynodiol diacetate, norethindrone, norethindrone
  • Preferred progestins are medroxyprogestrone, norethindrone and norethynodrel.
  • Exemplary bone resorption inhibiting polyphosphonates include polyphosphonates of the type disclosed in U.S. Pat. No. 3,683,080, granted Aug. 8, 1972, the disclosures of which are incorporated herein by reference.
  • Preferred polyphosphonates are geminal diphosphonates (also referred to as bis-phosphonates).
  • Tiludronate disodium is an especially preferred polyphosphonate.
  • Ibandronic acid is an especially preferred polyphosphonate.
  • Alendronate is an especially preferred polyphosphonate.
  • Other preferred polyphosphonates are 6-amino-1-hydroxy-hexylidene-bisphosphonic acid and 1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid.
  • the polyphosphonates may be administered in the form of the acid, or of a soluble alkali metal salt or alkaline earth metal salt. Hydrolyzable esters of the polyphosphonates are likewise included. Specific examples include ethane-1-hydroxy 1,1-diphosphonic acid, methane diphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic acid, methane dichloro diphosphonic acid, methane hydroxy diphosphonic acid, ethane-1-amino-1,1-diphosphonic acid, ethane-2-amino-1,1-diphosphonic acid, propane-3amino-1-hydroxy-1,1-diphosphonic acid, propane-N,N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, propane-3-3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenyl amino methane diphosphonic acid,N,N-dimethylamino methane diphosphonic acid
  • the compounds of this invention may be combined with a mammalian estrogen agonist/antagonist.
  • Any estrogen agonist/antagonist may be used as the second compound of this invention.
  • the term estrogen agonist/antagonist refers to compounds which bind with the estrogen receptor, inhibit bone turnover and prevent bone loss.
  • estrogen agonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and mimicking the actions of estrogen in one or more tissue.
  • Estrogen antagonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and blocking the actions of estrogen in one or more tissues.
  • a preferred estrogen agonist/antagonist is droloxifene: (phenol, 3-[1-[4[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-butenyl]-, (E)-) and associated compounds which are disclosed in U.S. Pat. No. 5,047,431 (the disclosure of which is hereby incorporated by reference).
  • Another preferred estrogen agonist/antagonist is tamoxifen: (ethanamine,2-[-4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl, (Z)-2-, 2-hydroxy-1,2,3-propanetricarboxylate(1:1)) and associated compounds which are disclosed in U.S. Pat. No. 4,536,516 (the disclosure of which is hereby incorporated by reference).
  • Another related compound is 4-hydroxy tamoxifen which is disclosed in U.S. Pat. No. 4,623,660 (the disclosure of which is hereby incorporated by reference).
  • a preferred estrogen agonist/antagonist is raloxifene: (methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-,hydrochloride) which is disclosed in U.S. Pat. No. 4,418,068 (the disclosure of which is hereby incorporated by reference).
  • Another preferred estrogen agonist/antagonist is toremifene: (ethanamine, 2-[4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl-, (Z)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) which is disclosed in U.S. Pat. No. 4,996,225 (the disdosure of which is hereby incorporated by reference).
  • centchroman 1-[2-[[4-(-methoxy-2,2, dimethyl-3-phenyt-chroman4-yl)-phenoxy]-ethyl]-pyrrolidine, which is disclosed in U.S. Pat. No. 3,822,287 (the disclosure of which is hereby incorporated by reference). Also preferred is levorneloxifene.
  • Another preferred estrogen agonist/antagonist is idoxifene: pyrrolidine, 1-[-[4-[[1-(4-iodophenyl)-2-phenyl-1-butenyl]phenoxy]ethyl] which is disclosed in U.S. Pat. No. 4,839,155 (the disclosure of which is hereby incorporated by reference).
  • Another preferred estrogen agonist/antagonist is 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol which is disclosed in U.S. Pat. No. 5,484,795 the disclosure of which is hereby incorporated by reference.
  • Another preferred estrogen agonist/antagonist is ⁇ 4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl ⁇ -[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone which is disclosed, along with methods of preparation, in PCT publication no. WO 95/10513 assigned to Pfizer Inc.
  • Another preferred estrogen agoinistantagonist is GW5638: 3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid; see Wilson, T. M. and coworkers in Endrocrinology 1997, 138, 9, 3901-3911.
  • estrogen agonist/antagonists include compounds as described in commonly assigned U.S. Pat. No. 5,552,412 the disclosure of which is hereby incorporated by reference. Especially preferred compunds described therein are:
  • a bone mass augmenting agent is a compound that augments bone mass to a level which is above the bone fracture threshold (as detailed in the World Health Organization Study World Health Organization, “Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a WHO Study Group. World Health Organization Technical Series 843”).
  • prostaglandin or prostaglandin agonist/antagonist may be used as the second compound of this invention (this would include utilizing two different compounds of Formula I of this inventon).
  • IGF-1 with or without IGF binding protein 3, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, growth hormone or growth hormone secretagogues may also be used.
  • PTH parathyroid hormone
  • active fragments of parathyroid hormone, growth hormone or growth hormone secretagogues may also be used.
  • the following paragraphs describe exemplary second compounds of this invention in greater detail.
  • prostaglandin may be used as the second compound of this invention.
  • prostagiandin refers to compounds which are analogs of the natural prostaglandins PGD 1 , PGD 2 , PGE 2 , PGE 1 and PGF 2 which are useful in the treatment of osteoporosis. These compounds bind to the prostaglandin receptors. Such binding is readily determined by those skilled in the art according to standard assays (e.g., An S. et al., Cloning and Expression of the EP 2 Subtype of Human Receptors for Prostaglandin E 2 , Biochemical and Biophysical Research Communications, 1993,197(1):263-270).
  • Prostaglandins are alicyclic compounds related to the basic compound prostanoic acid.
  • the carbon atoms of the basic prostaglandin are numbered sequentially from the carboxylic carbon atom through the cyclopentyl ring to the terminal carbon atom on the adjacent side chain. Normally the adjacent side chains are in the trans orientation.
  • the presence of an oxo group at C-9 of the cyclopentyl moiety is indicative of a prostaglandin within the E class while PGE 2 contains a trans unsaturated double bond at the C 13 -C 14 and a cis double bond at the C 5 -C 6 position.
  • prostaglandins are described and referenced below, however, other prostaglandins will be known to those skilled in the art. Exemplary prostaglandins are disclosed in U.S. Pat. Nos. 4,171,331 and 3,927,197 (the disclosures of which are hereby incorporated by reference).
  • prostaglandin agonistlantagonist refers to compounds which bind to prostaglandin receptors (e.g., J. W. Regan et al., Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmacologically Defined EP 2 Subtype, Molecular Pharmacology, 46: 213-220, 1994.) and mimic the action of prostaglandin in vivo (e.g., stimulate bone formation and increase bone mass and strength). Such actions are readily determined by those skilled in the art according to standard assays (Eriksen E. F.
  • Sodium fluoride may be used as the second compound of this invention.
  • the term sodium fluoride refers to sodium fluoride in all its forms (e.g., slow release sodium fluoride, sustained release sodium fluoride). Sustained release sodium fluoride is disclosed in U.S. Pat. No. 4,904,478, the disclosure of which is hereby incorporated by reference.
  • the activity of sodium fluoride is readily determined by those skilled in the art according to biological protocols (e.g., see Eriksen E. F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J. et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv.
  • parathyroid hormone refers to parathyroid hormone, fragments or metabolites thereof and structural analogs thereof which can stimulate bone formation and increase bone mass.
  • parathyroid hormone related peptides and active fragments and analogues of parathyroid related peptides see WO 94/01460.
  • Such functional activity is readily determined by those skilled in the art according to standard assays (e.g., see Eriksen E. F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J. et.
  • growth hormone secretagogue refers to compounds which stimulate the release of growth hormone or mimic the action of growth hormone (e.g., increase bone formation leading to increased bone mass). Such actions are readily determined by those skilled in the art according to standard assays. A variety of these compounds are included in the following published PCT patent applications: WO 95/14666; WO 95/13069; WO 94/19367; WO 94/13696; and WO 95/34311. However, other growth hormone or growth hormone secretagogues will be known to those skilled in the art.
  • a preferred growth hormone secretagogue is N-[1(R)-[1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4′-piperidin]-1′-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide:MK-677.
  • Some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in Formula I precursors).
  • remote functionality e.g., primary amine, secondary amine, carboxyl in Formula I precursors.
  • the need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis , John Wiley & Sons, New York, 1991.
  • the starting materials and reagents for the above described compounds are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis.
  • many of the compounds used therein are related to, or are derived from compounds found in nature, in which there is a large scientific interest and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.
  • Such compounds include, for example, prostaglandins.
  • Some of the compounds of this invention have asymmetric carbon atoms and therefore are enantiomers or diastereomers.
  • Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known per oe, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof are considered as part of this invention. Also, some of the compounds of this invention are atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • salts are within the scope of this invention and they can be prepared by conventional methods. For example, they can be prepared simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
  • the compounds of this invention are all adapted to therapeutic use as agents that stimulate bone formation and increase bone mass in mammals, particularly humans. Since bone formation is closely related to the development of osteoporosis and bone related disorders, these compounds, by virtue of their action on bone, prevent, arrest and/or regress osteoporosis.
  • the utility of the compounds of the present invention as medical agents in the treatment of conditions which present with low bone mass (e.g., osteoporosis) in mammals (e.g. humans, particularly the female) is demonstrated by the activity of the compounds of this invention in conventional assays, including the in vivo assay, a receptor binding assay, the Cyclic AMP assay and the Fracture healing assay (all of which are described below).
  • the in vivo assay (with appropriate modifications within the skill in the art) may be used to determine the activity of other anabolic agents as well as the prostaglandin agonists of this invention.

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010041673A1 (en) * 2000-04-13 2001-11-15 Fossa Anthony A. Combinations of corticotropin releasing factor antagonists and growth hormone secretagogues
US6407298B1 (en) * 1998-12-11 2002-06-18 Nissan Chemical Industries, Ltd. Process for the preparation of (p-chlorophenyl)propanol derivatives
US6426359B1 (en) 1996-12-20 2002-07-30 Pfizer Inc. Prevention and treatment of skeletal disorder with EP2 receptor subtype selective prostaglandin E2 agonists
WO2003053923A2 (en) 2001-12-20 2003-07-03 Applied Research Systems Ars Holding N.V. Pyrrolidine derivatives as prostaglandin modulators
US6649657B2 (en) * 1996-12-20 2003-11-18 Pfizer Inc. Prevention of loss and restoration of bone mass by certain prostaglandin agonists
US20040042982A1 (en) * 2002-09-04 2004-03-04 Rosenberg E. William Composition and method for treating soft nails
US20050065133A1 (en) * 2003-09-19 2005-03-24 Pfizer Inc Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and an EP2 or EP4 selective agonist
US20050182030A1 (en) * 2001-05-10 2005-08-18 American Pharmaceutical Partners, Inc. Liquid injectable formulation of disodium pamidronate
US20050203086A1 (en) * 2004-03-04 2005-09-15 Pfizer Inc. Methods of treatment using an EP2 selective receptor agonist
US20050288357A1 (en) * 2002-06-10 2005-12-29 Applied Research Systems Ars Holding N.V. Gamma lactams as prostaglandin agonists and use thereof
US20080045545A1 (en) * 2006-07-28 2008-02-21 Pfizer Inc. Ep2 agonists
WO2008152388A1 (en) * 2007-06-14 2008-12-18 Opal Drug Discovery Limited Silicon-containing compounds for treatment or prevention of bone loss or restoration of bone mass, or augmentation of bone mass
US20090118316A1 (en) * 2004-06-21 2009-05-07 Pfzer Inc. Methods for Augmenting Bone
US7696243B2 (en) 2004-12-06 2010-04-13 Merck Serono, S.A. Pyrrolidin-2-one derivatives for use as DP1 receptor agonists
WO2010116270A1 (en) 2009-04-10 2010-10-14 Pfizer Inc. Ep2/4 agonists
US20100317712A1 (en) * 1995-01-09 2010-12-16 Cameron Kimberly O Estrogen Agonists/Antagonists For Preventing Breast Cancer
US20140296294A1 (en) * 2011-12-15 2014-10-02 University Of Pittsburgh -- Of The Commonwealth System Of Higher Education Novel cannabinoid receptor 2 (cb2) inverse agonists and therapeutic potential for multiple myeloma and osteoporosis bone diseases
US9968716B2 (en) 2013-10-15 2018-05-15 Ono Pharmaceutical Co., Ltd. Drug-eluting stent graft

Families Citing this family (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA67754C2 (uk) * 1997-10-10 2004-07-15 Пфайзер, Інк. Агоністи простагландину, фармацевтична композиція на їх основі (варіанти), спосіб нарощення та збереження кісткової маси у хребетних та спосіб лікування (варіанти)
EP1000619A3 (de) * 1998-06-23 2002-07-24 Pfizer Products Inc. Verfahren zur Behandlung von Glaukoma
ES2232434T3 (es) 1999-03-05 2005-06-01 Duke University Analogos de prostaglandinas c-16 fp selectivas insaturadas.
EP1108426A3 (de) * 1999-12-02 2002-10-02 Pfizer Products Inc. Anwendung von Prostaglandinagonisten zur Behandlung der Erektionstörungen und Impotenz
IL141120A0 (en) 2000-01-31 2002-02-10 Pfizer Prod Inc Use of prostaglandin (pge2) receptor 4 (epa) selective agonists for the treatment of acute and chronic renal failure
WO2001068592A1 (en) * 2000-03-13 2001-09-20 Eli Lilly And Company Sulfonamide derivatives
US20020172693A1 (en) 2000-03-31 2002-11-21 Delong Michell Anthony Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US20020013294A1 (en) 2000-03-31 2002-01-31 Delong Mitchell Anthony Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US6472372B1 (en) * 2000-12-06 2002-10-29 Ortho-Mcneil Pharmaceuticals, Inc. 6-O-Carbamoyl ketolide antibacterials
US6713455B2 (en) 2001-09-17 2004-03-30 Ortho-Mcneil Pharmaceutical, Inc. 6-O-carbamate-11,12-lacto-ketolide antimicrobials
CN1599598A (zh) 2001-11-30 2005-03-23 美国辉瑞有限公司 骨生长促进性化合物的控释聚合组合物
IL161834A0 (en) * 2001-11-30 2005-11-20 Pfizer Prod Inc Pharmaceutical compositions and methods for administering ep2 receptor selective agonists
WO2003048140A1 (fr) 2001-12-03 2003-06-12 Japan Tobacco Inc. Compose azole et utilisation medicinale de celui-ci
CA2469304A1 (en) 2001-12-05 2003-06-19 Ortho-Mcneil Pharmaceutical, Inc. 6-o acyl ketolide antibacterials
JP2006021998A (ja) * 2002-07-18 2006-01-26 Ono Pharmaceut Co Ltd Ｅｐ２アゴニストを有効成分とする月経困難症治療剤
EP1563846B1 (de) 2002-10-10 2012-08-29 Ono Pharmaceutical Co., Ltd. Endogene reparaturfaktoren herstellende promoter
US20070270489A1 (en) 2003-07-25 2007-11-22 Ono Pharmaceutical Co., Ltd. Remedy for Cartilage-Related Diseases
US7318925B2 (en) * 2003-08-08 2008-01-15 Amgen Fremont, Inc. Methods of use for antibodies against parathyroid hormone
BR0318454A (pt) 2003-08-08 2006-09-12 Abgenix Inc anticorpos dirigidos a hormÈnio da paratireóide (pth) e seus usos
US7183310B2 (en) * 2004-08-10 2007-02-27 Allergan, Inc. Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents
US7906552B2 (en) 2004-08-10 2011-03-15 Allergan, Inc. Cyclopentane heptan(ENE)OIC acid, 2-heteroarylalkenyl derivatives as therapeutic agents
JP4893999B2 (ja) 2004-10-22 2012-03-07 小野薬品工業株式会社 吸入用医薬組成物
US7645755B2 (en) 2004-10-22 2010-01-12 Janssen Pharmaceutical N.V. Inhibitors of c-fms kinase
NZ555289A (en) 2004-10-22 2010-10-29 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
CA2610692C (en) 2005-06-03 2014-11-25 Ono Pharmaceutical Co., Ltd. Ep2 agonists which may have an ep3 agonistic effect for regeneration and/or protection of nerves
US20060281788A1 (en) 2005-06-10 2006-12-14 Baumann Christian A Synergistic modulation of flt3 kinase using a flt3 inhibitor and a farnesyl transferase inhibitor
US7915316B2 (en) 2005-08-22 2011-03-29 Allergan, Inc Sulfonamides
NZ572073A (en) 2006-04-20 2011-09-30 Janssen Pharmaceutica Nv Heterocyclic compounds as inhibitors of c-fms kinase
JP5331681B2 (ja) 2006-04-20 2013-10-30 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ｃ−ｆｍｓキナーゼの阻害剤
US8697716B2 (en) 2006-04-20 2014-04-15 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
JO3240B1 (ar) 2007-10-17 2018-03-08 Janssen Pharmaceutica Nv c-fms مثبطات كيناز
JP5136640B2 (ja) 2008-03-12 2013-02-06 宇部興産株式会社 ピリジルアミノ酢酸化合物
US8685986B2 (en) 2009-03-30 2014-04-01 Ube Industries, Ltd. Medical composition for treatment or prophylaxis of glaucoma
WO2011078303A1 (ja) 2009-12-25 2011-06-30 宇部興産株式会社 アミノピリジン化合物
US9090584B2 (en) 2010-01-26 2015-07-28 Allergan, Inc. Therapeutic agents for treatment of ocular hypertension
JOP20180012A1 (ar) 2012-08-07 2019-01-30 Janssen Pharmaceutica Nv عملية السلفنة باستخدام نونافلوروبوتانيسولفونيل فلوريد
WO2014025675A1 (en) 2012-08-07 2014-02-13 Janssen Pharmaceutica Nv Process for the preparation of heterocyclic ester derivatives
US20150272874A1 (en) 2012-10-29 2015-10-01 Cardio Incorporated Pulmonary disease-specific therapeutic agent
SG11201507976YA (en) 2013-03-28 2015-10-29 Ube Industries Substituted biaryl compound
KR102006862B1 (ko) * 2019-01-07 2019-08-02 주식회사 하이센스바이오 신규한 펩타이드
CN114805120A (zh) * 2022-05-23 2022-07-29 江苏瑞达环保科技有限公司 一种间氰甲基苯甲酸甲酯的合成工艺

Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE51251C (de) W. LANGENBRUCH in Düren, Rheinl., Kölnstr. 68 b Sicherheitslampe für Bergwerke
US3894065A (en) 1973-04-27 1975-07-08 Merck & Co Inc Aryl-oxo-alkanoic acids
US3987091A (en) 1973-04-12 1976-10-19 Merck & Co., Inc. 11,12-secoprostaglandins
US3989749A (en) 1973-10-17 1976-11-02 Merck & Co., Inc. 11,12-Secoprostaglandins
US3991106A (en) 1974-09-13 1976-11-09 Merck & Co., Inc. 16-Ethers of 8-aza-9-dioxothia-11,12-seco-prostaglandins
US3991087A (en) 1973-12-13 1976-11-09 Merck & Co., Inc. 8-Halo-11,12-secoprostaglandins
US4018802A (en) 1975-04-09 1977-04-19 Merck & Co., Inc. 9-Thia- and oxothia- and 9-dioxothia-11,12-seco-prostaglandins and processes
US4020177A (en) 1974-08-30 1977-04-26 Merck & Co., Inc. Substituted phenoxy-tridecanoic acids
GB1478281A (en) 1974-08-30 1977-06-29 Merck & Co Inc 11,12-secoprostaglandins
US4033996A (en) 1973-04-25 1977-07-05 Merck & Co., Inc. 8-Aza-9-oxo(and dioxo)-thia-11,12-secoprostaglandins
GB1479158A (en) 1974-12-18 1977-07-06 Basford A Furniture
US4055596A (en) 1974-09-13 1977-10-25 Merck & Co., Inc. 11,12-Seco-prostaglandins
US4055597A (en) 1973-01-26 1977-10-25 Merck & Co., Inc. 10-Aza-11,12-secoprostaglandins
US4066692A (en) 1972-10-30 1978-01-03 Merck & Co., Inc. 11,12-secoprostaglandins
US4087435A (en) 1977-02-17 1978-05-02 Merck & Co., Inc. 8-Aza-9-dioxothiaprostanoic acids
US4091107A (en) 1973-04-25 1978-05-23 Merck & Co., Inc. 8-Aza-9-oxo(and dioxo)-thia-11,12-secoprostaglandins
US4092356A (en) 1972-10-30 1978-05-30 Merck & Co., Inc. 11,12-Secoprostaglandins
US4097504A (en) 1975-04-23 1978-06-27 Merck & Co., Inc. 11,12-Secoprostaglandins
US4112236A (en) 1977-04-04 1978-09-05 Merck & Co., Inc. Interphenylene 8-aza-9-dioxothia-11,12-secoprostaglandins
US4150235A (en) 1976-12-17 1979-04-17 Merck & Co., Inc. Interphenylene 11,12-secoprostaglandins
US4175203A (en) 1976-12-17 1979-11-20 Merck & Co., Inc. Interphenylene 11,12-secoprostaglandins
US4243678A (en) 1977-12-30 1981-01-06 Byk Gulden Lomberg Chemische Fabrik Gmbh Acylhydrocarbylaminoalkanoic acids, compositions and uses
BE897566A (fr) 1982-08-20 1983-12-16 Midit Derives d'acides w-amines, leur preparation et utilisation ainsi que les compositions contenant ces derives.
US5140038A (en) 1988-08-31 1992-08-18 Boehringer Mannheim Gmbh Sulphonamidocycloalkane compounds, pharmaceutical compositions containing them, and methods of use thereof
EP0605193A1 (de) 1992-12-22 1994-07-06 Eli Lilly And Company Verwendung von Benzothiophene zur Behandlung von Hypercholesterolämie
US5332730A (en) 1992-10-16 1994-07-26 Allergan, Inc. Azido derivatives of cyclopentane heptanoic or heptenoic acid
WO1995006664A1 (en) 1993-08-31 1995-03-09 Merck Frosst Canada Inc. Dna encoding prostaglandin receptor ep2
US5607978A (en) 1992-09-21 1997-03-04 Allergan Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
WO1997027174A1 (fr) * 1996-01-23 1997-07-31 Shionogi & Co., Ltd. Derives d'acides amines sulfones et inhibiteurs de metalloproteinases contenant ces derives
US5658897A (en) 1996-04-08 1997-08-19 Allergan Cyclopentane(ene) heptanoic or cyclopentane(ene) heptenoic acid, 2-hydrocarbyl phosphinyloxyalkyl or phosphonamidoalkyl as therapeutic agents
WO1998027976A1 (en) 1996-12-20 1998-07-02 Pfizer Inc. Prevention and treatment of skeletal disorder with ep2 receptor subtype selective prostaglandin e2 agonists
NZ336394A (en) 1998-06-23 2000-11-24 Pfizer Prod Inc use of tetrazolyl or carboxylic acid derivatives to treat glaucoma

Family Cites Families (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE512251C (de) 1930-01-24 1930-11-07 Koch & Sterzel Akt Ges Verfahren zum Einstellen der Kapazitaet eines auf Induktionswirkung beruhenden elektrischen Apparates, insbesondere Stromwandlers
FR897566A (fr) * 1942-08-28 1945-03-26 Bopp & Reuther Gmbh Machine à rotors
US3442890A (en) 1965-06-15 1969-05-06 Mead Johnson & Co Substituted 3-benzazocin-16-ones
CH549555A (de) 1969-04-02 1974-06-14 Byk Gulden Lomberg Chem Fab Verfahren zur herstellung von cylierten anilinocarbonsaeuren oder deren salze.
DE1917006B2 (de) 1969-04-02 1971-09-23 Siemens AG, 1000 Berlin u. 8000 München Elektrooptischer regelkreis zum regeln der lichtpunktinten sitaet einer kathodenstrahlroehre
US3780095A (en) 1970-04-08 1973-12-18 Byk Gulden Lomberg Chem Fab Acylated anilino-carboxylic acids and their salts
JPS5019756A (de) 1973-06-25 1975-03-01
SE7414770L (de) * 1973-12-13 1975-06-16 Merck & Co Inc
US4210749A (en) 1974-11-12 1980-07-01 Pennwalt Corporation Substituted 1,2,4,5-tetrahydro-3H,3 benzazepines
GB2012170B (en) * 1977-12-24 1982-09-02 Fisons Ltd Pesticidal and platn growth regulant compounds and composiions
AT368358B (de) 1977-12-24 1982-10-11 Fisons Ltd Schaedlingsbekaempfungs- und pflanzenwachstumsregulierungsmittel
US4803197A (en) 1987-01-12 1989-02-07 Ciba-Geigy Corporation 2,1-benzothiazepine-2,2-dioxide-5-carboxylic acid derivatives
DE3719046A1 (de) 1987-06-06 1988-12-15 Basf Ag Verwendung von salzen von sulfonamidcarbonsaeuren als korrosionsinhibitoren in waessrigen systemen
US5084466A (en) 1989-01-31 1992-01-28 Hoffmann-La Roche Inc. Novel carboxamide pyridine compounds which have useful pharmaceutical utility
US5081152A (en) 1989-07-05 1992-01-14 Kotobuki Seiyaku Co., Ltd. Azulene derivatives as thromboxane a2 and prostaglandin endoperoxide receptor antagonist
EP0505467A1 (de) 1989-12-16 1992-09-30 Astra Pharmaceuticals Limited Pharmakologisch aktive dicarbonsäure-monoamidderivate
ES2036926B1 (es) 1991-08-08 1994-01-16 Uriach & Cia Sa J "procedimiento para la obtencion de derivados de la (2-alquil-3-piridil)metilpiperazina".
US6743929B1 (en) * 1992-08-25 2004-06-01 G. D. Searle & Co. Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
EP0617009B1 (de) 1992-10-15 1999-09-08 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Neues aminosäurederivat
US5578593A (en) 1992-12-11 1996-11-26 Merck & Co., Inc. Spiro piperidines and homologs promote release of growth hormone
HUT72076A (en) 1992-12-11 1996-03-28 Merck & Co Inc Process for preparing spiro piperidines and homologs which promote release of growth hormone and pharmaceutical compositions containing them
US5455258A (en) 1993-01-06 1995-10-03 Ciba-Geigy Corporation Arylsulfonamido-substituted hydroxamic acids
HUT74733A (en) 1993-11-09 1997-02-28 Merck & Co Inc Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone
CA2176140A1 (en) 1993-11-24 1995-06-01 Meng Hsin Chen Indolyl group containing compounds and the use thereof to promote the release of growth hormone(s)
JPH07334432A (ja) * 1994-06-07 1995-12-22 Hitachi Ltd メモリ制御回路
US5777112A (en) 1994-06-13 1998-07-07 Merck & Co., Inc Piperazine compounds promote release of growth hormone
AU5772296A (en) 1995-05-19 1996-11-29 Chiroscience Limited 3,4-disubstituted-phenylsulphonamides and their therapeutic use
AU6764396A (en) 1995-08-08 1997-03-05 Thomas Jefferson University Recombinant c-proteinase and processes, methods and uses thereof
JP3843145B2 (ja) * 1995-12-25 2006-11-08 株式会社ルネサステクノロジ 同期型半導体記憶装置
DE19603033A1 (de) 1996-01-19 1997-07-24 Schering Ag Perfluoralkylhaltige Metallkomplexe, Verfahren zu deren Herstellung und ihre Verwendung in der NMR-Diagnostik
CA2242416C (en) 1996-01-23 2006-03-21 Shionogi & Co., Ltd. Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same
DK0946502T3 (da) * 1996-10-11 2003-04-07 Abbott Gmbh & Co Kg Sulfonamidinhibitorer for det interleukin-1beta-omdannende enzym
UA59384C2 (uk) * 1996-12-20 2003-09-15 Пфайзер, Інк. Похідні сульфонамідів та амідів як агоністи простагландину, фармацевтична композиція та способи лікування на їх основі
SI0966436T1 (en) * 1997-02-21 2003-04-30 Bayer Aktiengesellschaft Aryl sulfonamides and analogues thereof and their use in the treatment of neurodegenerative diseases
TW378330B (en) * 1997-06-03 2000-01-01 Fujitsu Ltd Semiconductor memory device
US5910923A (en) * 1997-10-23 1999-06-08 Texas Instruments Incorporated Memory access circuits for test time reduction
US6436989B1 (en) * 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
US6436914B1 (en) * 1998-06-30 2002-08-20 Bristol-Myers Squibb Company 2-hydroxy-3—(4-hydroxy-3-sulfonamidophenyl)—propylamines useful as beta 3 adrenergic agonists
US6069829A (en) * 1998-09-29 2000-05-30 Texas Instruments Incorporated Internal clock multiplication for test time reduction
US6246619B1 (en) * 2000-02-07 2001-06-12 Vanguard International Semiconductor Corp. Self-refresh test time reduction scheme
WO2001090056A1 (en) * 2000-05-19 2001-11-29 Eli Lilly And Company Sulfonamide derivatives
AU2002234165A1 (en) * 2000-11-03 2002-05-27 Tularik, Inc. Combination therapy using pentafluorobenzenesulfonamides and antineoplastic agents

Patent Citations (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE51251C (de) W. LANGENBRUCH in Düren, Rheinl., Kölnstr. 68 b Sicherheitslampe für Bergwerke
US4092356A (en) 1972-10-30 1978-05-30 Merck & Co., Inc. 11,12-Secoprostaglandins
US4066692A (en) 1972-10-30 1978-01-03 Merck & Co., Inc. 11,12-secoprostaglandins
US4055597A (en) 1973-01-26 1977-10-25 Merck & Co., Inc. 10-Aza-11,12-secoprostaglandins
US3987091A (en) 1973-04-12 1976-10-19 Merck & Co., Inc. 11,12-secoprostaglandins
US4091107A (en) 1973-04-25 1978-05-23 Merck & Co., Inc. 8-Aza-9-oxo(and dioxo)-thia-11,12-secoprostaglandins
US4033996A (en) 1973-04-25 1977-07-05 Merck & Co., Inc. 8-Aza-9-oxo(and dioxo)-thia-11,12-secoprostaglandins
US3894065A (en) 1973-04-27 1975-07-08 Merck & Co Inc Aryl-oxo-alkanoic acids
US3989749A (en) 1973-10-17 1976-11-02 Merck & Co., Inc. 11,12-Secoprostaglandins
US3991087A (en) 1973-12-13 1976-11-09 Merck & Co., Inc. 8-Halo-11,12-secoprostaglandins
GB1478281A (en) 1974-08-30 1977-06-29 Merck & Co Inc 11,12-secoprostaglandins
US4020177A (en) 1974-08-30 1977-04-26 Merck & Co., Inc. Substituted phenoxy-tridecanoic acids
US4055596A (en) 1974-09-13 1977-10-25 Merck & Co., Inc. 11,12-Seco-prostaglandins
US3991106A (en) 1974-09-13 1976-11-09 Merck & Co., Inc. 16-Ethers of 8-aza-9-dioxothia-11,12-seco-prostaglandins
GB1479158A (en) 1974-12-18 1977-07-06 Basford A Furniture
US4018802A (en) 1975-04-09 1977-04-19 Merck & Co., Inc. 9-Thia- and oxothia- and 9-dioxothia-11,12-seco-prostaglandins and processes
US4097504A (en) 1975-04-23 1978-06-27 Merck & Co., Inc. 11,12-Secoprostaglandins
US4150235A (en) 1976-12-17 1979-04-17 Merck & Co., Inc. Interphenylene 11,12-secoprostaglandins
US4175203A (en) 1976-12-17 1979-11-20 Merck & Co., Inc. Interphenylene 11,12-secoprostaglandins
US4087435A (en) 1977-02-17 1978-05-02 Merck & Co., Inc. 8-Aza-9-dioxothiaprostanoic acids
US4112236A (en) 1977-04-04 1978-09-05 Merck & Co., Inc. Interphenylene 8-aza-9-dioxothia-11,12-secoprostaglandins
US4243678A (en) 1977-12-30 1981-01-06 Byk Gulden Lomberg Chemische Fabrik Gmbh Acylhydrocarbylaminoalkanoic acids, compositions and uses
BE897566A (fr) 1982-08-20 1983-12-16 Midit Derives d'acides w-amines, leur preparation et utilisation ainsi que les compositions contenant ces derives.
US5140038A (en) 1988-08-31 1992-08-18 Boehringer Mannheim Gmbh Sulphonamidocycloalkane compounds, pharmaceutical compositions containing them, and methods of use thereof
US5407951A (en) 1988-08-31 1995-04-18 Boehringer Mannheim Gmbh Sulphonamidocycloalkane compounds, pharmaceutical compositions containing them, and methods of use thereof
US5607978A (en) 1992-09-21 1997-03-04 Allergan Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
US5332730A (en) 1992-10-16 1994-07-26 Allergan, Inc. Azido derivatives of cyclopentane heptanoic or heptenoic acid
EP0605193A1 (de) 1992-12-22 1994-07-06 Eli Lilly And Company Verwendung von Benzothiophene zur Behandlung von Hypercholesterolämie
WO1995006664A1 (en) 1993-08-31 1995-03-09 Merck Frosst Canada Inc. Dna encoding prostaglandin receptor ep2
US5605814A (en) 1993-08-31 1997-02-25 Merck Frosst Canada Inc. DNA encoding human prostaglandin receptor EP2
US5759789A (en) 1993-08-31 1998-06-02 Merck Frosst Canada, Inc. Prostaglandin receptor EP2
WO1997027174A1 (fr) * 1996-01-23 1997-07-31 Shionogi & Co., Ltd. Derives d'acides amines sulfones et inhibiteurs de metalloproteinases contenant ces derives
US5658897A (en) 1996-04-08 1997-08-19 Allergan Cyclopentane(ene) heptanoic or cyclopentane(ene) heptenoic acid, 2-hydrocarbyl phosphinyloxyalkyl or phosphonamidoalkyl as therapeutic agents
WO1998027976A1 (en) 1996-12-20 1998-07-02 Pfizer Inc. Prevention and treatment of skeletal disorder with ep2 receptor subtype selective prostaglandin e2 agonists
NZ336394A (en) 1998-06-23 2000-11-24 Pfizer Prod Inc use of tetrazolyl or carboxylic acid derivatives to treat glaucoma

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
A. Scutt, et al., "PGE2 Induces the Transition from Non-Adherent to Adherent Bone Marrow Mesenchymal Precursor Cells Via a cAMP/EP2-Mediated Mechanism" Prostaglandins 49:383-395, 1995.
Bicking, J. B. et al., "J. Med. Chem." 1983, 26, pp. 335-341, "11,12-Secoprostaglandins. 6. Interphenylene Analogues of Acylhydroxyalkanoic Acids and Related Compounds as Renal Vasodilators".
Bicking, J.B. et al., "J. Med. Chem." Oct. 1978, vol. 21, No. 10 pp. 1011-1018, "11,12-Secoprostaglandins. 5. 8-Acetyl- or 8-(1-Hydroxyethyl)-12-hydroxy-13-aryloxtridecanoic Acids and Sulfonamide Isosteres as Inhibitors of Platelet Aggregation".
Bicking, J.B. et al., "Journal of Medicinal Chemistry", 1977, vol. 20, No. 1, pp. 35-43, 11,12-Secoprostaglandins. 1. Acylhydroxyalkanoic Acids and Related Compounds.
Billman, J. H. et al., "J. Org. Chem." May 1961, vol. 26, pp. 1437-1440, "Reduction of Schiff Bases. III. Reduction with Dimethylamine Borane".
Bolander, M. E. et al., "38th Annual Mtg Orthopaedic Research Society" Feb. 17-20, 1992, Washington D.C., p. 138, "Estrogen treatment during fracture repair strengthens healing callus in an osteoporotic model".
Busetti, V. et al., "Recueil des Travaux Chimiques des Pays-Bas" May 1987, vol. 106, No. 5, pp. 151-156, "Crystal and molecular structure of N-acetyl N-hydroxy alpha-amino acids".
Busetti, V. et al., "Recueil des Travaux Chimiques des Pays-Bas" May 1987, vol. 106, No. 5, pp. 151-156, "Crystal and molecular structure of N-acetyl N-hydroxy α-amino acids".
Florence N. Woodiel, et al., "Anabolic Effects of Prostaglandins in Cultured Fetal Rate Calvariae: Structure-Activity Relations and Signal Transduction Pathway" Journal of Bone and Mineral Research, vol. 11 No. 9, 1996, pp. 1249-1255.
Fukumoto, S, et al., "Journal of Medicinal Chemistry", 1992, vol. 35, No. 12, pp. 2202-2209, "Antagonistic Activity of Phenol Derivatives".
Jones, J. H. et al., "J. Med. Chem." Oct. 1977, vol. 20, No. 10 pp. 1299-1304, "11,12-Secoprostaglandins. 4. 7-(N-Alkylmethanesulfonamido)heptanoic Acids".
Jones, J. H. et al., "Journal of Medicinal Chemistry", 1977, vol. 20, No. 1, pp. 44-48, 11,12-Secoprostaglandins. 2. N-Acyl-N-alkyl-7-aminoheptanoic Acids.
Ludwig, B. J. et al., "J. Med. Chem." Jul. 1967, vol. 10, No. 4, pp. 556-564, "The Synthesis of Hydroxylamine Derivatives Possessing Hypocholesteremic Activity".
Regan, J. W. et al., "American Society for Pharmacology and Experimental Therapeutics" 1994, vol. 46, pp. 213-220, "Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmacologically Defined Ep2 Subtype".
Robert L. Smith, et al, "Prostaglandin Isosteres. 1. (8-Aza-, 8, 10-Diaza-, and 8-Aza-11-thia)-9-oxoprostanoic Acids and Their Derivatives", Journal of Medicinal Chemistry, 1977, vol. 20, No. 10, pp. 1292-1299.
Smith, R. L. et al., "Journal of Medicinal Chemistry", 1977, vol. 20, No. 10, pp. 1292-1299, "Prostaglandin Isosteres. 1. (8-Aza-a, 8,10-Diaza-, and 8-Aza-11-thia)-9-oxoprostanoic Acids and Their Derivatives".
Smith, R. L. et al., "Journal of Medicinal Chemistry", 1977, vol. 20, No. 4, pp. 540-547, "11,12-Secoprostaglandins. 3. 8-Alkylthio(sulfinyl and sulfonyl)-12-hydroxyalkanoic Acids and Related Compounds".

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